NCT00923845

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

Completed Phase 2 Results posted Last updated 29 September 2017

What this trial tests

Phase 2 trial testing Pentostatin in Renal Cell Carcinoma in 25 participants. Completed in 22 June 2017.

Timeline

1 March 2008

Primary endpoint
1 June 2015

22 June 2017

Quick facts

Lead sponsor	National Cancer Institute (NCI)
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	25
Start date	1 March 2008
Primary completion	1 June 2015
Estimated completion	22 June 2017
Sites	1 location across United States

Drugs / interventions tested

• Pentostatin (PENTOSTATIN) — full drug profile →
• Sirolimus (sirolimus) — full drug profile →
• Cyclophosphamide (cyclophosphamide) — full drug profile →
• Allogeneic Hematopoietic Stem Cell Transplant (HSCT) — full drug profile →
• Th2 rapa cells
• Donor Lymphocyte Harvest
• Induction Therapy
• GVHD prophylaxis
• Donor Hematopoietic Stem Cell Harvest

Conditions studied

• Renal Cell Carcinoma — all drugs for Renal Cell Carcinoma →
• Graft-Versus-Host Disease — all drugs for Graft-Versus-Host Disease →
• Engraftment Syndrome — all drugs for Engraftment Syndrome →

Sponsor

National Cancer Institute (NCI)

Who can join

Adults 18 to 75, any sex, with Renal Cell Carcinoma or Graft-Versus-Host Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Clinical Regression of Metastatic Renal Cell Carcinoma (Partial Response (PR)) or Complete Remission of Tumor (Complete Response (CR)) Primary · 6 Months Post-Transplant (Day +100)

Response was assessed by computed tomography measurements and the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the largest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target le

Partial Response (PR)

Group	Value	95% CI
Recipient	0

Complete Response (CR)

Group	Value	95% CI
Recipient	0

Progressive Disease (PD)

Group	Value	95% CI
Recipient	8

Stable Disease (SD)

Group	Value	95% CI
Recipient	1

Not Applicable (NA)

Group	Value	95% CI
Recipient	1

Count of Participants With Adverse Events Secondary · 50 months and 6 days

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Group	Value	95% CI
Donor	0
Recipient	12

Count of Patients Having Neutropenia Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen Secondary · During the 21-day PC regimen

Absolute neutrophil count determination by complete blood count methodology (Absolute Neutrophil Count (ANC) \< 500 Cells/µL).

Group	Value	95% CI
Recipient	0

Count of Patients Having an Infectious Complication Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen Secondary · During the 21-day PC regimen

Occurrence of infection by Common Terminology Criteria for Adverse Events (CTCAE).

Group	Value	95% CI
Recipient	0

Immune Depletion in Cluster of Differentiation 4 (CD4) Cells Secondary · Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen)

Reduction in cluster of differentiation 4 (CD4)+ T cells \[change in median values and (range of values)\].

Baseline

Group	Value	95% CI
Recipient	503	124 – 1487

Day 21

Group	Value	95% CI
Recipient	54	10 – 107

Immune Depletion in Cluster of Differentiation 8 (CD8)+ T Cells Secondary · Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen)

Reduction in cluster of differentiation 8 (CD8)+ T cells \[change in median values and (range of values)\].

Baseline

Group	Value	95% CI
Recipient	239	56 – 770

Day 21

Group	Value	95% CI
Recipient	45	12 – 131

Immune Suppression Secondary · Cytokine analysis at baseline and within 24 hours of completion of the pentostatin/cyclophosphamide regimen

Immune suppression is defined by the frequency of elimination of a pre-transplant T cell cytokine value.

Positive at baseline

Group	Value	95% CI
Recipient	100

Negative at baseline

Group	Value	95% CI
Recipient	0

Positive 24 hours after regimen

Group	Value	95% CI
Recipient	0

Negative 24 hours after regimen

Group	Value	95% CI
Recipient	100

Engraftment Donor T Cell and Myeloid Cell Chimerism Secondary · Days 14, 28, 45, and 60 post transplant

Donor Genetic Elements by variable number tandem repeat-polymerase chain reaction (VNTR-PCR) Analysis.

Day 14 donor T cell chimerism

Group	Value	95% CI
Recipient	61	7 – 77

Day 28 donor T cell chimerism

Group	Value	95% CI
Recipient	72	9 – 91

Day 45 donor T cell chimerism

Group	Value	95% CI
Recipient	74	21 – 88

Day 60 donor T cell chimerism

Group	Value	95% CI
Recipient	77	26 – 95

Day 14 myeloid cell chimerism

Group	Value	95% CI
Recipient	0	0 – 27

Day 28 myeloid cell chimerism

Group	Value	95% CI
Recipient	13	4 – 50

Day 45 myeloid cell chimerism

Group	Value	95% CI
Recipient	18	11 – 67

Day 60 myeloid cell chimerism

Group	Value	95% CI
Recipient	26	13 – 76

Count of Patients With Grade II or Greater Acute Graft Versus Host Disease (GVHD) in First 100 Days Post-Transplant Secondary · 100 days post transplant

Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD grading criteria. Acute GVHD may include rash, diarrhea, and liver damage (i.e. rash Grading: \<25% body surface area (BSA) = 1, rash 25-50% BSA = 2, generalized erythroderma = 3, and desquamation and bullae = 4); liver Grading: total bilirubin 2-3 mg/dl = 1, total bilirubin 3-6 mg/dl =2, total bilirubin 6-15 mg/dl =3, and total bilirubin \>15 mg/dl = 4)).

Group	Value	95% CI
Recipient	0

Count of Patients With Late Acute Graft Versus Host Disease (GVHD) After Day 100 Post-Transplant Secondary · 100 days post-transplant through 5 years post-transplant

Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD grading criteria. Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD grading criteria. Acute GVHD may include rash, diarrhea, and liver damage (i.e. rash Grading: \<25% body surface area (BSA) = 1, rash 25-50% BSA = 2, generalized erythroderma = 3, and desquamation and bullae = 4); liver Grading: total bilirubin 2-3 mg/dl = 1, total bilirubin 3-6 mg/dl =2, total bilirubin 6-15 mg/dl =3, and total bilirubin \>15 mg/dl = 4)).

Group	Value	95% CI
Recipient	4

Count of Patients With Chronic Graft Versus Host Disease (GVHD) Secondary · For the duration of post-transplant follow-up

Chronic GVHD was assessed by the 2005 Chronic GVHD Consensus Project. Chronic GVHS may include dryness of the mouth and eyes, weight loss, liver damage and lung damage leading to cough and shortness of breath (i.e. skin Grading: no symptoms = 0, \<18% body surface area (BSA) = 1, 19-50% BSA = 2, and \>50% BSA = 3); oral cavity Grading: no symptoms = 0, mild symptoms = 1, moderate symptoms =2 and severe symptoms =3)).

Group	Value	95% CI
Recipient	1

Cluster of Differentiation 4 (CD4) T Cells Immune Reconstitution Secondary · Days 14, 60, and 100 post transplant

CD4 T Cells immune reconstitution is defined as distribution of CD4+ T cells subsets within naïve, central memory, effector memory, and effector memory-RA cells analyzed by flow cytometry.

Day 14

Group	Value	95% CI
Recipient	22	± 3

Day 60

Group	Value	95% CI
Recipient	20	± 2

Day 100

Group	Value	95% CI
Recipient	19	± 2

Adverse events — posted to ClinicalTrials.gov

Time frame: 50 months and 6 days. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Donor

Serious: 0/13 (0%)

Deaths: 0/13

Recipient

Serious: 8/12 (67%)

Deaths: 7/12

Serious adverse events (11 terms)

Reaction	System	Donor	Recipient
Death not associated with CTCAE term::Disease progression NOS	General disorders	—	—
Death not associated with CTCAE term::Death NOS	General disorders	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Blood	Blood and lymphatic system disorders	—	—
Allergic reaction/hypersensitivity (including drug fever)	Immune system disorders	—	—
Dysphagia (difficulty swallowing)	Gastrointestinal disorders	—	—
Hemorrhage, GI::Lower GI NOS	Gastrointestinal disorders	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Urinary tract NOS	Renal and urinary disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Pleural effusion (non-malignant)	Respiratory, thoracic and mediastinal disorders	—	—
Rash/desquamation	Skin and subcutaneous tissue disorders	—	—
Vomiting	Gastrointestinal disorders	—	—

Other adverse events (106 terms — click to expand)

Reaction	System	Donor	Recipient
Hemoglobin	Blood and lymphatic system disorders	—	—
Leukocytes (total WBC)	Blood and lymphatic system disorders	—	—
Phosphate, serum-low (hypophosphatemia)	Metabolism and nutrition disorders	—	—
Sodium, serum-low (hyponatremia)	Metabolism and nutrition disorders	—	—
AST, SGOT(serum glutamic oxaloacetic transaminase)	Hepatobiliary disorders	—	—
Neutrophils/granulocytes (ANC/AGC)	Blood and lymphatic system disorders	—	—
ALT, SGPT (serum glutamic pyruvic transaminase)	Hepatobiliary disorders	—	—
Albumin, serum-low (hypoalbuminemia)	Hepatobiliary disorders	—	—
Fatigue (asthenia, lethargy, malaise)	General disorders	—	—
Pain - Other	General disorders	—	—
Platelets	Blood and lymphatic system disorders	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Neurology - Other	Nervous system disorders	—	—
Pleural effusion (non-malignant)	Respiratory, thoracic and mediastinal disorders	—	—
Thrombosis/embolism (vascular access-related)	Cardiac disorders	—	—
Acidosis (metabolic or respiratory)	Metabolism and nutrition disorders	—	—
Bilirubin (hyperbilirubinemia)	Metabolism and nutrition disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Dermatology/Skin - Other	Skin and subcutaneous tissue disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Dyspnea (shortness of breath)	Respiratory, thoracic and mediastinal disorders	—	—
Potassium, serum-high (hyperkalemia)	Metabolism and nutrition disorders	—	—
Rash/desquamation	Skin and subcutaneous tissue disorders	—	—
Alkaline phosphatase	Hepatobiliary disorders	—	—
Anorexia	Gastrointestinal disorders	—	—
Cardiac Arrhythmia - Other	Cardiac disorders	—	—
Cardiac General - Other	Cardiac disorders	—	—
Confusion	Nervous system disorders	—	—
Creatinine	Renal and urinary disorders	—	—
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	General disorders	—	—
Glucose, serum-high (hyperglycemia)	Metabolism and nutrition disorders	—	—
Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis)	Blood and lymphatic system disorders	—	—
Hemorrhage, GU::Urinary NOS	Renal and urinary disorders	—	—
Hypertension	Cardiac disorders	—	—
Hypotension	Cardiac disorders	—	—
Infection - Other	Infections and infestations	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Urinary tract NOS	Renal and urinary disorders	—	—
Mucositis/stomatitis (clinical exam)::Oral cavity	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Pain::Back	Musculoskeletal and connective tissue disorders	—	—

Most-reported serious reactions: Death not associated with CTCAE term::Disease progression NOS, Death not associated with CTCAE term::Death NOS, Infection with normal ANC or Grade 1 or 2 neutrophils::Blood, Allergic reaction/hypersensitivity (including drug fever), Dysphagia (difficulty swallowing), Hemorrhage, GI::Lower GI NOS, Infection with normal ANC or Grade 1 or 2 neutrophils::Urinary tract NOS, Nausea.

Data from ClinicalTrials.gov NCT00923845 adverse events section.

Sponsor's own description

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).

Publications & conference data

7 peer-reviewed publications reference this trial (live from Europe PMC):

1. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention.
   Kaufhold S, Bonavida B. · · 2014 · cited 342× · PMID 25084828 · DOI 10.1186/s13046-014-0062-0
2. Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs.
   Shelton J, Lu X, Hollenbaugh JA, Cho JH, et al · · 2016 · cited 219× · PMID 27960273 · DOI 10.1021/acs.chemrev.6b00209
3. Trial watch: Chemotherapy with immunogenic cell death inducers.
   Vacchelli E, Galluzzi L, Fridman WH, Galon J, et al · · 2012 · cited 98× · PMID 22720239 · DOI 10.4161/onci.1.2.19026
4. The hypoxia-adenosine link during inflammation.
   Bowser JL, Lee JW, Yuan X, Eltzschig HK. · · 2017 · cited 90× · PMID 28798196 · DOI 10.1152/japplphysiol.00101.2017
5. Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts.
   Mossoba ME, Onda M, Taylor J, Massey PR, et al · · 2011 · cited 36× · PMID 21521777 · DOI 10.1158/1078-0432.ccr-11-0493
6. High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses.
   Mossoba ME, Halverson DC, Kurlander R, Schuver BB, et al · · 2015 · cited 12× · PMID 26071480 · DOI 10.1158/1078-0432.ccr-15-0340
7. Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after.
   Tykodi SS, Sandmaier BM, Warren EH, Thompson JA. · · 2011 · cited 4× · PMID 21417772 · DOI 10.1517/14712598.2011.566855