Clinical trial NCT00923845: Low-Intensity Stem Cell Transplantation With Multiple Lymphocyte Infusions to Treat Advanced Kidney Cancer
Official title: Low Intensity Allogeneic Hematopoietic Stem Cell Transplantation Therapy of Metastatic Renal Cell Carcinoma Using Early and Multiple Donor Lymphocyte Infusions Consisting of Sirolimus-Generated Donor Th2 Cells
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Graft-Versus-Host Disease
Engraftment Syndrome
Keywords: Metastatic Renal Cell Carcinoma
Allogeneic Hematopoietic Stem Cell Transplant
Th2 Cells
Sirolimus
Pentostatin
Kidney Cancer
Renal Cell Carcinoma
Metastatic Renal Cell Cancer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2009-06-18
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

Low-dose chemotherapy is easier for the body to tolerate than typical high-dose chemotherapy and involves a shorter period of complete immune suppression.

Donor immune cells called lymphocytes, or T cells, fight residual tumor cells that might have remained in the recipients body after stem cell transplant, in what is called a graft-versus-tumor (GVT) effect.

The immune-suppressing drug sirolimus appears to help prevent graft-versus-host disease (GVHD), a side effect of stem cell transplant in which donated T cells sometimes attack healthy tissues, damaging organs such as the liver, intestines and skin.

Th2 cells are cells collected from the transplant donor and grown in a high concentration of sirolimus.

Objectives:

To determine whether stem cell transplantation using low-dose chemotherapy and sirolimus-generated Th2 cells can cause a remission of advanced kidney cancer.

Eligibility:

Patients between 18 and 75 years of age who have kidney cancer that has spread beyond the kidney and who have a tissue-matched sibling stem cell donor.

Design:

Patients undergo stem cell transplantation as follows:

* Low-intensity chemotherapy with pentostatin and cyclophosphamide over a 21-day period to reduce the level of the immune system to prepare for the transplant. Pentostatin is given through a vein (intravenous (IV)) on days 1, 8 and 15; cyclophosphamide tablets are taken by mouth for 21 consecutive days.
* Sirolimus tablets, taken by mouth, starting 2 days before the transplant and continuing until 60 days after the transplant.
* IV infusions of stem cells and Th2 cells.

Following the transplant, patients have the following procedures:

* Additional Th2 cell infusions on days 14 and 45 after the transplant.
* Follow-up visits at the National Institutes of Health (NIH) Clinical Center twice a week for the first 6 months after the transplant and then less frequently for at least 5 years to evaluate response to treatment and treatment side effects. Evaluations include a bone marrow aspirate and biopsy 1 month after transplant and periodic blood tests and imaging procedures (e.g., computed tomography (CT) or magnetic resonance imaging (MRI) scans).

Detailed description: 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.

Eligibility criteria: * 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).

Primary outcomes:
measure: Clinical Regression of Metastatic Renal Cell Carcinoma (Partial Response (PR)) or Complete Remission of Tumor (Complete Response (CR))
timeFrame: 6 Months Post-Transplant (Day +100)
Secondary outcomes:
measure: Count of Participants With Adverse Events
timeFrame: 50 months and 6 days
measure: Count of Patients Having Neutropenia Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen
timeFrame: During the 21-day PC regimen
measure: Count of Patients Having an Infectious Complication Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen
timeFrame: During the 21-day PC regimen
measure: Immune Depletion in Cluster of Differentiation 4 (CD4) Cells
timeFrame: Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen)
measure: Immune Depletion in Cluster of Differentiation 8 (CD8)+ T Cells
timeFrame: Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen)
measure: Immune Suppression
timeFrame: Cytokine analysis at baseline and within 24 hours of completion of the pentostatin/cyclophosphamide regimen
measure: Engraftment Donor T Cell and Myeloid Cell Chimerism
timeFrame: Days 14, 28, 45, and 60 post transplant
measure: Count of Patients With Grade II or Greater Acute Graft Versus Host Disease (GVHD) in First 100 Days Post-Transplant
timeFrame: 100 days post transplant
measure: Count of Patients With Late Acute Graft Versus Host Disease (GVHD) After Day 100 Post-Transplant
timeFrame: 100 days post-transplant through 5 years post-transplant
measure: Count of Patients With Chronic Graft Versus Host Disease (GVHD)
timeFrame: For the duration of post-transplant follow-up
measure: Cluster of Differentiation 4 (CD4) T Cells Immune Reconstitution
timeFrame: Days 14, 60, and 100 post transplant
measure: Cluster of Differentiation 8 (CD8)+ T Cells Immune Reconstitution
timeFrame: Days 14, 60, and 100 post transplant
measure: Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the Th2 Transcription Factor GATA Binding Protein 3 (GATA-3)
timeFrame: Days 14, 60 and 100 post transplant
measure: Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the Th1 Transcription Factor T-bet
timeFrame: Days 14, 60, and 100 post transplant
measure: Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the T-reg Transcription Factor Forkhead Box P3 (FoxP3))
timeFrame: Days 14, 60, and 100 post transplant
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Daniel H Fowler, M.D.
role: PRINCIPAL_INVESTIGATOR
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citation: Mossoba ME, Halverson DC, Kurlander R, Schuver BB, Carpenter A, Hansen B, Steinberg SM, Ali SA, Tageja N, Hakim FT, Gea-Banacloche J, Sportes C, Hardy NM, Hickstein DD, Pavletic SZ, Khuu H, Sabatini M, Stroncek D, Levine BL, June CH, Mariotti J, Rixe O, Fojo AT, Bishop MR, Gress RE, Fowler DH. High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses. Clin Cancer Res. 2015 Oct 1;21(19):4312-20. doi: 10.1158/1078-0432.CCR-15-0340. Epub 2015 Jun 12.