Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Fibrinolytic Agents

Anticoagulants

Nivolumab

Heparin

Calcium heparin

FFPE, blood samples (liquid biopsy, heparin and EDTA blood) performed in patients presenting a renal metastatic cancer receiving treatment as standard practice according to physician's choice (2nd or 3rd line of treatment with nivolumab, or other second line according to physician's choice)

Immunological and tumour characterization

Stefania Scala, MD, PhD

Sandro Pignata, MD, PhD

The project aims to identify Nivolumab predictive biomarkers in metastatic renal cancer patients through functional evaluation of peripheral Tregs and NKs. Moreover the efficacy of new CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/ US2013/0079292A1) will be ex vivo evaluated in modulating Tregs and NKs function

Renal cell carcinomas (RCCs) is a disease with an estimated 338,000 new cases diagnosed worldwide. Approximately 30% of patients present with metastatic disease. Since November 2015 the human IgG4 anti-PD-1 monoclonal antibody, Nivolumab, was approved to treat advanced (metastatic) clear cell renal cell carcinoma (ccRCC) patients who have received a prior anti-angiogenic therapy. PD-1 (also know as CD279), is an immune checkpoint receptor (ICR) expressed on the surface of T cells. The binding with its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) expressed on tumour cells, stromal cells or both suppress effector T cells activation and inflammatory activity promoting self-tolerance and allowing cancer cells to evade immune system. Despite encouraging results in multiple solid tumors the clinical anti-PD1 response is not as wide as expected due to multiple immuno-escape mechanisms; moreover there aren't biomarkers to predict or follow RCC patient's response to Nivolumab.

Immune evasion comprise the recruitment of immunosuppressive cells and reduced access of T-effector cells to tumor microenvironment. T-regulatory cells (Tregs) suppress a whole range of immune cells and ICRs regulate generation and/or suppression of their function. Immune cell access to tumor is controlled by the chemokine CXCL12, CXCR4 ligand. CXCL12 repels tumor-specific effector T cells and recruits suppressive cell populations at tumor sites. von Hippel-Lindau (VHL) gene mutations, detectable in 70% of RCC patients, regulate immune response inducing PD-L1 expression and promoting Natural Killer (NK) cells function. Thus NK function is a crucial element in nivolumab sensitivity.

The project will enroll patients receiving Nivolumab in 2nd or 3rd line treatment for metastatic ccRCC and, as control cohorts, either everolimus or axitinib.

Aims of the project are:

* To evaluate Tregs function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment. Ex vivo effect of CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/ US2013/0079292A1) and other Tregs targets antagonists (ICOS,CD39/CD73) or agonists (TLR7L) as putative anti-PD1 resistance mechanisms
* To evaluate NK function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment. Ex vivo effect of CXCR4 antagonists

Archival FFPE specimen.

Blood samples performed during standard visits and not requiring additional blood tests:

* Heparin blood
* EDTA blood

Nivolumab in mRCC Patients: Treg Function, T-cell Access and NK Interactions to Predict and Improve Efficacy

Treg function will be mesured as % inhibition of T-effector proliferation (Tregs/T-effector 1:1 ratio). %T-effector proliferation in the presence of patients derived Tregs (Tregs/T-effector 1:1). Ex vivo effect of CXCR4 antagonists ( PCT/IB2011/000120; EP 2 528 936 B1/US2013/0079292A1) and other Tregs targets antagonists (ICOS, CD39/CD73) or agonists (TLR7L) will be assessed to identify novel anti-PD1 resistance mechanisms.

NK cytotoxicity will be measured as % NK cell degranulation (CD107a assay), intracellular staining Grz A and GrzB and intracellular cytokines, GM-CSF, IFNγ, IL-10, TNF. Ex vivo effect of CXCR4 antagonists will be evaluated on NK cytotoxicity.

The effect of anti-PD1 and CXCR4 antagonists on tumor and tumor microenvironment cells will be evaluated in:

* Immunocompetent model (RENCA): % tumor growth; % positive cells Granzyme/ Foxp3
* Human xenograft model (786 cell): % tumor growth

National Cancer Institute, Naples

Blood and Lymph Conditions

Immune System Diseases

Symptoms and General Pathology

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Lymphoma

Pathologic Complete Response

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Disease Progression

Disease Attributes

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Lymphosarcoma

Antirheumatic Agents

Anti-Infective Agents

Cyclophosphamide

Plerixafor

Busulfan

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Patients will receive reduced Busulfan and Cyclophosphamide (BUCY) 2 conditioning regimen, consisting in the administration of two medications: Busulfan and Cyclophosphamide Plus: CXCR4 Antagonist. Then they will undergo a Hematopoietic Stem Cell Transplantation (Autologous or Allogeneic)

12mg/kg, Oral, divided in 4 days, 3mg/kg/day Oral, during days -7, -6, -5 y -4.

80mg/kg, Intravenous (IV), divided in 2 days, 40mg/kg/day IV, during days -3 y -2.

24mg, Subcutaneous (SC), in one day, 24mg/day SC, during day -4.

CXCR4 Antagonist

Peripheral blood HSC (autologous HSCT) or Bone Marrow HSC (allogeneic HSCT) transfusion, day 0

Hematopoietic Stem Cell Transplantation

Eucario Leon Rodriguez, M.D.

Monica M Rivera Franco, M.D.,MSc

Monica M Rivera Franco, M.D.

The purpose of this study is to evaluate the disease free survival and the overall survival in patients with acute leukemia in first or second complete remission after administrating a CXCR4 antagonist, as a chemo sensitization strategy, plus chemotherapy as the conditioning regimen for autologous or allogeneic hematopoietic stem cell transplantation (HSCT).

In the last decade, HSCT has become an efficient strategy for the treatment of many malignant and non-malignant hematological diseases, being the most common, according to the European Bone Marrow Transplantation (EBMT), acute leukemias. Both myeloid and lymphoid acute leukemias are considered malignant clonal diseases of the hematopoietic stem cells, and represent a therapeutic challenge due to the high relapse rate and mortality using conventional chemotherapy regimens. HSC reside mainly within the bone marrow, protected by a microenvironment or niche, which is perivascular, created partly by mesenchymal stromal cells and endothelial cells. Interactions between these cells and many adhesion molecules are considered a key factor for growing, transformation, and migration of neoplastic cells. The main pathway involved in the cellular transit regulation is chemokine receptor 4 (CXCR4) and its chemokine ligand 12 (CXCL12), responsible of mediating interactions between the HSC and stromal cells, and whose blocking through other cytokines and antagonists of the CXCR4 receptor (plerixafor) favors chemotaxis and HSC output to peripheral blood. Such strategy has become an effective technique to increase mobilization and harvesting in patients undergoing stem cell transplantations.

On the other hand, some preclinical studies have shown that the activation of CXCL12 pathway favors tumor growth, promoting survival and invasion of the malignant cells, recruiting stromal cells that facilitate their proliferation and promote angiogenesis directly. In such way, this pathway has been considered a therapeutic target to block their activity and inhibit tumor progression.

Patients with acute leukemia in first or second complete remission undergoing autologous or allogeneic hematopoietic stem cell transplantation (HSCT), commonly present low response rates and low survival due to persistent minimal residual disease, despite conventional high dose chemotherapy regimens. It is necessary to create strategies to increase the destruction rate of neoplastic cells in patients with acute leukemia candidates to HSCT. Our hypothesis is that the administration of a CXCR4 antagonist as part of the conditioning regimen in patients with acute leukemia candidates to HSCT will allow the mobilization and sensitization of leukemia blast cells, eradicating efficiently the minimal residual disease, responsible of posterior relapse, and will achieve a higher response rate and survival of patients undergoing this procedure.

Chemo Sensitization Before Hematopoietic Stem Cell Transplantation in Patients With Acute Leukemia in Complete Remission

Chemo Sensitization Before Hematopoietic Stem Cell Transplantation With a CXCR4 Antagonist in Patients With Acute Leukemia in Complete Remission: Pilot Study

Time from HSCT to relapse of the underlying disease.

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Tin Fluorides

Imatinib Mesylate

Patients with chronic phase CML on Imatinib therapy (400 mg/day) achieving less than an optimal response will be treated with sc injections of BL-8040, while continuing Imatinib. The first part of the study will include escalating dose groups. Up to 4 dose levels will be investigated starting at dose level 1. Patients will be accrued in a conventional 3+3 design. Applying this study design, the first cohort of 3 patients will be treated at dose level 1 (0.5 mg/kg) on Day 1, 15, 29 and 43. Patients will continue taking Imatinib 400 mg/day throughout the study. Dose escalation will continue until the maximal tolerated dose (MTD) is established and protocol specific stopping rules for toxicity are met. If no MTD is reached, dose escalation will continue up to dose level 4 (1.25 mg/kg).

BL-8040 will be added to imatinib to improve CML response.

BL-8040

Arnon Nagler, MD

The aim of the study is to test the safety and efficacy of BL-8040 (a CXCR4 antagonist) in improving the response to imatinib in CML patients not achieving an optimal response with imatinib alone.

To improve cytogenetic and molecular response of CML patients receiving Imatinib, who have not achieved an optimal response according to European LeukemiaNet (ELN) definitions , or MR4 after 24 months with Imatinib. This will be achieved by addition of the CXCR4 antagonist BL-8040, mobilizing CML leukemia stem cells from their protective bone marrow niche and exposing them to Imatinib and BL-8040-mediated apoptosis.

Imatinib and BL-8040 (Novel Anti CXCR4 Antagonist) for Improving Molecular Response in Chronic Myelogenous Leukemia

Phase I/II Study Using Imatinib and s.c. BL-8040 (Novel Anti CXCR4 Antagonist) for Improving Molecular Response in Chronic Myelogenous Leukemia (CML) Patients in First Chronic Phase Achieving Less Than Optimal Response With Imatinib.

The investigators will test CXCR4 receptor occupancy and expression and additional pharmacodynamic endpoints relevant to CXCR4 inhibition.

The investigators will assess the safety of the BL-8040 by grading of toxicities according to standard Common Toxicity Criteria for Adverse Effects (CTCAE) criteria.

The cytogenetic and molecular response will be assessed by standard FISH and PCR test according to established criteria.

Sheba Medical Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab in mRCC Patients: Treg Function, T-cell Access and NK Interactions to Predict and Improve Efficacy	NCT03891485	RCC Metastatic Rena...	Immunological a...	-	National Cancer Institute, Naples
Chemo Sensitization Before Hematopoietic Stem Cell Transplantation in Patients With Acute Leukemia in Complete Remission	NCT02605460	Acute Myeloid L... Acute Lymphoid ...	Busulfan Cyclophosphamid... CXCR4 Antagonis... Hematopoietic S...	18 Years - 60 Years	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Imatinib and BL-8040 (Novel Anti CXCR4 Antagonist) for Improving Molecular Response in Chronic Myelogenous Leukemia	NCT02115672	Chronic Myeloid...	BL-8040	18 Years - 70 Years	Sheba Medical Center
Imatinib and BL-8040 (Novel Anti CXCR4 Antagonist) for Improving Molecular Response in Chronic Myelogenous Leukemia	NCT02115672	Chronic Myeloid...	BL-8040	18 Years - 70 Years	Sheba Medical Center

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