Low-Intensity Stem Cell Transplantation With Multiple Lymphocyte Infusions to Treat Advanced Kidney Cancer

Background:

Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially effective
treatment option for patients with metastatic renal cell carcinoma (RCC).

In a pilot clinical trial in refractory hematologic malignancy subjects, we have found that
augmentation of a T cell-replete allograft with donor Th2 cells generated ex vivo in
sirolimus (rapamycin; Th2.rapa cells) allows prompt donor engraftment after
outpatient-intensity chemotherapy. This transplant approach has been associated with a low
incidence of acute graft versus host disease (GVHD).

Based on these data, we seek to safely achieve objective clinical regression of metastatic
RCC by the following new transplant approach. (1) The allograft will be administered after a
low intensity, outpatient induction chemotherapy regimen consisting of pentostatin and
cyclophosphamide. This regimen is intended to provide sufficient host immune T cell
depletion, and as such, a conventional preparative regimen will not be administered. (2) To
avoid mixed chimerism for rapid potentiation of graft-versus-tumor (GVT) effects, a growth
colony stimulating factor (G-CSF) mobilized allograft will be augmented with donor lymphocyte
infusion at day 14 post-transplant consisting of Th2.rapa cells.

Objectives:

Primary objective: (1) Determine whether this new, low-intensity transplant approach can
yield objective partial or complete remission of metastatic RCC, with the goal of ruling out
a partial response (PR)/complete response (CR) rate of 20% in favor of a rate of 60%.

Secondary objectives: (1) Evaluate the safety and immune-depleting properties of the
pentostatin/cyclophosphamide regimen; (2) Characterize the engraftment kinetics and GVHD
profile of this new transplant approach; and (3) Characterize post-transplant immunity in
study subjects, including cytokine phenotype, immune reconstitution, and potential anti-tumor
effector mechanisms.

Eligibility:

Adults (18 - 75 years) with metastatic RCC who have an eligible 6/6 human leukocyte antigen
(HLA)-matched sibling donor.

Must have had one prior therapy with either sorafenib, sunitinib, or temsirolimus or any
other Food and Drug Administration (FDA)-approved agent for therapy of metastatic renal cell
carcinoma..

Life expectancy greater than or equal to 3 months, Karnofsky score greater than or equal to
80, relatively normal organ function, and absence of central nervous system (CNS) metastases.

Design:

Patients will receive a 21-day course of pentostatin (intravenous infusion on days 1, 8, and
15; 4 mg/m^2 per dose) and daily oral cyclophosphamide (200 mg per day).

Patients will receive a mobilized, T cell-replete allogeneic hematopoietic stem cell graft
followed by a pre-emptive donor lymphocyte infusion with donor Th2 cells at day 14
post-transplant. GVHD prophylaxis will consist of a short-course of sirolimus plus
maintenance therapy with cyclosporine A.

If greater than or equal to 2/5 partial or complete responses are observed within 6 months
post-transplant, the therapy will be considered potentially promising, and will be expanded
in a Simon two-stage design to evaluate a total of n = 14 subjects. If greater than or equal
to 5/14 PR/CR are achieved, the therapy will be considered worthy of further investigation.

- INCLUSION CRITERIA: Recipient

Diagnosis of metastatic renal cell carcinoma, either clear cell type or non-clear cell
type. The diagnosis must be confirmed by the Laboratory of Pathology of National Cancer
Institute (NCI) or Hackensack (there will be no central pathology review).

The consent process will include a discussion of the potential role of high-dose
interleukin-2 (IL-2) therapy prior to protocol enrollment. High-dose IL-2 therapy is not
widely available, but may be available on an NCI protocol (Dr. Yang) or through Dr. Alter
for Hackensack patients. IL-2 therapy may also be administered by any other qualified
physician; the Novartis web-site has a list of such physicians. For subjects who are deemed
to be eligible for high-dose IL-2 and elect to receive this therapy, such subjects must
have progressive disease post-IL-2 to enter this study; such subjects must also have
received and have had progressive disease after therapy with one of the agents listed
below.

Subject must have progressive disease after therapy consisting of one of the following Food
and Drug Administration (FDA)-approved agents: sorafenib, sunitinib, or temsirolimus.

Patients 18 - 75 years of age. Subjects older than 75 will not be enrolled due to an
increased rate of transplant-related complications.

Must have consenting sibling matched at 6/6 human leukocyte antigen (HLA) antigens (A, B,
DR).

Patient or legal guardian must be able to give informed consent.

All previous therapy must be completed at least 2 weeks prior to study entry. Any grade 3
or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or
less.

Karnofsky performance status greater than or equal to 80%.

Life expectancy of at least 3 months.

Left ventricular ejection fraction greater than 40% (multi-gated acquisition scan (MUGA) or
echo) within 28 days of enrollment.

Carbon monoxide diffusing capacity (DLCO) greater than 50% of expected value (hemoglobin
(Hb) corrected), obtained within 28 days of enrollment.

Creatinine clearance greater than or equal to 40 ml/min. Creatinine clearance will be
determined by testing of a 24 hour urine collection and simultaneous serum creatinine
value. In previous studies, the creatine clearance of patients with metastatic renal cell
cancer who underwent nephrectomy was 53 plus or minus 19.

Serum total bilirubin less than 2.5 mg/dl, and serum alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) values less than or equal to 2.5 times the upper limit of
normal. ALT and AST values above these levels may be accepted (up to a maximum of 5 times
the upper limit of normal), at the discretion of the principal investigator (PI) or study
chairperson, if such elevations are thought to be due to liver involvement by malignancy.

INCLUSION CRITERIA : Donor

Sibling who is 6/6 HLA-matched with recipient.

Ability to give informed consent.

Age 18 years to 80 years. Donors older than 80 will not be eligible due to potentially
increased complications from the donation procedure.

Adequate venous access for peripheral apheresis, or consent to use a temporary central
venous catheter for apheresis.

Donors must be human immunodeficiency virus (HIV) negative, hepatitis B surface antigen
negative, and hepatitis C antibody negative. This is to prevent the possible transmission
of these infections to the recipient. Donors with a history of hepatitis B or hepatitis C
infections may be eligible. However, eligibility determination of such patients will
require a hepatology consultation. The risk/benefit of the transplant and the possibility
of transmitting hepatitis will be discussed with the patient and eligibility will then be
determined by the principal investigator.

A donor who is lactating must substitute formula feeding for her infant during the period
of cytokine administration. Filgrastim may be secreted in human milk, although its
bioavailability from this source is not known. Limited clinical data suggest that
administration of filgrastim or to neonates is not associated with adverse outcomes.

EXCLUSION CRITERIA: Recipient

Active infection that is not responding to antimicrobial therapy.

Active central nervous system (CNS) involvement by malignancy.

HIV infection. There is theoretical concern that the degree of immune suppression
associated with the treatment may result in progression of HIV infection.

Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients
with concomitant positive hepatitis B surface antigen, patient will require a hepatology
consultation. The risk/benefit profile of transplant and hepatitis B will be discussed with
the patient and eligibility determined by the principal investigator and protocol
chairperson.

Hepatitis C infection. Patient may have hepatitis C infection. However, each patient will
require a hepatology consultation. The risk/benefit profile of transplant and hepatitis C
will be discussed with the patient and eligibility determined by the principal investigator
and protocol chairperson.

Pregnant or lactating. Patients of childbearing potential must use an effective method of
contraception from the time of study entry to at least one year post-transplant; effective
methods include intrauterine device (IUD), hormonal (birth control pills, injections, or
implants), tubal ligation/hysterectomy, partner s vasectomy, or barrier methods (condom,
diaphragm, or cervical cap). Males on the protocol, and their partners of child-bearing
potential, must also use an effective form of contraception at study entry and for one year
post-transplant. The effects of the chemotherapy, the subsequent transplant, and the
medications used after the transplant are highly likely to be harmful to a fetus. The
effects upon breast milk are also unknown and may be harmful to the infant; therefore,
women should not breastfeed during the interval from study entry to one year
post-transplant.

History of psychiatric disorder which may compromise compliance with transplant protocol,
or which does not allow for appropriate informed consent (as determined by principal
investigator or study chairman).

EXCLUSION CRITERIA: Donor

History of psychiatric disorder which may compromise compliance with transplant protocol,
or which does not allow for appropriate informed consent.

History of hypertension that is not controlled by medication, stroke, or severe heart
disease. Individuals with symptomatic angina will be considered to have severe heart
disease and will not be eligible to be a donor.

No other medical contraindications to stem cell donation (i.e. severe atherosclerosis,
autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular
accident). Patients with a history of coronary artery bypass grafting or angioplasty will
receive a cardiology evaluation and be considered on a case-by-case basis.

History of prior malignancy. However, cancer survivors who have undergone potentially
curative therapy may be considered for stem cell donation on a case-by-case basis. The
risk/benefit of the transplant and the possibility of transmitting viable tumor cells at
the time of transplantation will be discussed with the patient.

Donors must not be pregnant. The effects of cytokine therapy on a fetus are unknown. Donors
of childbearing potential must use an effective method of contraception from the time of
study entry until at least one year post-transplant.

Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per
microliter).