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Idelalisib

Enzyme Inhibitors

Idelalisib is an orally-administered, selective inhibitor of Phosphoinositide 3 kinase (PI3K)-delta which has been shown to be extremely effective in inducing partial to complete responses in many B-cell derived malignancies.

intervention: 100mg Idelalisib twice daily beginning +90(+/- 10) days after allo HSCT and continued through Day 270 post transplant

Placebo to be taken twice daily beginning +90(+/- 10) days after allo HSCT and continued through Day 270 post transplant

100mg BID beginning on day 90 (+/- 10days) and continuing until day 270 post transplant.

Idelalisib 100 MG

Placebo Oral Tablet

Douglas Gladstone, MD

This is a study to evaluate the safety of idelalisib as post-transplantation maintenance in patients with B cell hematologic malignancies undergoing a allogeneic hematopoietic stem cell transplant (HSCT). Safety will be evaluated through the assessment of cytopenias, effect on donor chimerism, effect on the incidence and severity of acute graft versus host disease, and gastro-intestinal tolerance.

Currently, to improve overall survival, the focus of the BMT program at JHH the introduction of anti-neoplastic therapy post transplantation: where the allo BMT serves as a platform to allowing a new intolerant immune system to interact with the post allo BMT intervention.

The importance of post BMT therapy has been made evident with tyrosine kinase inhibition (TKI) in Philadelphia chromosome positive acute lymphocytic leukemia (ALL) and chronic myeloid leukemia(CML), where patients who had disease progression while on TKI therapy pre-allo BMT enjoy marked improvement in overall survival when TKI is part of a maintenance program; the use of DNA hypomethylation agents after allo BMT for relapsed myeloid malignances; or the use of rituximab after allo BMT in follicular lymphoma.

Idelalisib, an orally-administered, selective inhibitor of Phosphoinositide 3 kinase (PI3K), is extremely effective in inducing partial responses to complete responses in many B-cell derived malignancies and should be studied in the post alloHSCT setting. Johns Hopkins Hospital has one of the world's largest experiences with alloHSCT. This study proposes a double blinded randomized phase I placebo trial where all patients who have undergone alloHSCT for a B-cell derived hematologic malignancy be offered either idelalisib 100mg or placebo twice daily for 180 days starting approximately 90 days after their HSCT.

Idelalisib 100mg or placebo twice daily, starting day +90 (+-/ 10 days) after transplant until day +270.

Idelalisib Post Allogeneic Hematopoietic Stem Cell Transplant (HSCT) in B Cell Derived Malignancies

Idelalisib Post Allogeneic Hematopoietic Stem Cell Transplant (HSCT) in B Cell Derived Malignancies: A Phase 1 Double Blinded Randomized Placebo Toxicity Trial

The evaluation of the safety of Idelalisib as post-transplantation maintenance in patients with B cell hematologic malignancies

Impact of Idelalisib on aGVHD, relapse, and non-relapse mortality

Search for Biomarkers which could better identify which patients would respond to treatment with Idelalisib in the post-transplant setting.

Gilead Sciences

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Idelalisib is an orally-administered, selective inhibitor of Phosphoinositide 3 kinase (PI3K)-delta which has been shown to be extremely effective in inducing partial to complete responses in many B-cell derived malignancies.

intervention: 100mg Idelalisib twice daily beginning +90(+/- 10) days after allo HSCT and continued through Day 270 post transplant

Idelalisib 100 MG: 100mg BID beginning on day 90 (+/- 10days) and continuing until day 270 post transplant.

Idelalisib 100mg

Placebo to be taken twice daily beginning +90(+/- 10) days after allo HSCT and continued through Day 270 post transplant

Placebo Oral Tablet: placebo

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Douglas Gladstone

Treatment-limiting Toxicities Will be Defined as Idelalisib Interruption for >14 Days, or Other >3 Adverse Events as Defined by CTCAE IV Not Captured in the Protocol for Dose De-escalation.

Event Free Survival at One Year.

Exploratory gene expression analysis of immune biomarkers in bone marrow aspirates and whole or targeted exome sequencing of lymphoma cells was not was not performed on any samples for this study. This study was terminated early due to safety concerns. Samples collected were not analyzed due to an initial lack of lab staffing during COVID then were destroyed after this sponsor/investigator left Johns Hopkins.

Identify Potential Predictive Biomarker Candidates Based on Exploratory Gene Expression Analysis of Immune Biomarkers in Bone Marrow Aspirates and Whole or Targeted Exome Sequencing of Lymphoma Cells

Overall Study

Ibrutinib

Florence CYMBALISTA, MD PD

Assessment of the mutational profile of the residual clone and the distribution of lymphocyte subpopulations at 3 years of treatment with ibrutinib

This project has an epidemiological part: to establish the percentage of patients, in a real-life situation, still undergoing treatment 3 years after its initiation, as well as a biological part: to determine the evolution of the clone and the prevalence of BTK mutations and PLCg2 in the absence of clinical or biological criteria for scalability.

Tolerance and Resistance to Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL

Tolerance and Resistance to Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL): Analysis of Real-life Data: "Snapshot" at 3 Years From the End of Ibrutinib ATU. A National Study of the FILO-LLC Group

In the long term, this study will help to draft new recommendations from FILO-LLC concerning the detection of resistance and the management of patients.

French Innovative Leukemia Organisation

Acute Graft Versus Host Disease

Alemtuzumab

Chlorambucil

Antineoplastic Agents, Immunological

alemtuzumab

Medical Monitor

This is a Phase III, open-label, multicenter, randomized, comparative study of Campath versus chlorambucil as front line therapy in patients with progressive B-Cell Lymphocytic Leukemia (B-CLL). Eligible patients must have previously untreated, Rai stage I-IV disease, and be experiencing progression of their B-CLL requiring treatment. Patients who meet all eligibility criteria may be randomized on a 1:1 basis to receive either Campath or chlorambucil. An estimated 284 patients (142 per treatment arm) from approximately 40 or more investigational sites will be randomized to one of the two treatment arms.

Efficacy/Safety of Frontline Alemtuzumab (Campath, MabCampath) vs Chlorambucil in Patients With Progressive B-Cell Lymphocytic Leukemia

A Phase III Study to Evaluate the Efficacy and Safety of Front-Line Therapy With Alemtuzumab (Campath, MabCampath) vs Chlorambucil in Patients With Progressive B-Cell Chronic Lymphocytic Leukemia

Genzyme, a Sanofi Company

Hematologic Neoplasms

Andrea Aroldi

Mantle-cell Lymphoma (MCL) is a B-cell non-Hodgkin's lymphoma (NHL) with heterogeneous behavior,ranging from indolent phenotype to highly aggressive and drug resistant cases with dismal prognosis.Disease progression and drug resistance may be generated by Tumor Microenvironment (TME),owing that M2-like immunosuppressive tumor associated macrophages (TAM) are pathologically functional in providing survival signals to MCL cells-and TME is known to help mask tumoral cells from host immune system.Similarly, Chronic Lymphocytic Leukemia (CLL) is a B-cell malignancy characterized by increased circulating number of mature B lymphocytes that eventually reside into bone marrow and lymphoid tissues as well.Higher number of circulating abnormal B cells is secondary to a balance between increased proliferation and decreased apoptosis activities,sustained by signals also deriving from TME.As a matter of fact,TME harbors different cell compounds and monocyte-derived Nurse-like cells (NLCs) resemble the M2-like macrophage immunosuppressive profile and turned out to be an important component able to interact with CLL cells, providing improvement of proliferation and survival.Recently, cancer-expressed CD47 was found to be involved in tumor immune escape through interaction with Signal Regulatory Protein-α (SIRP-α) expressed by TAM,being able to quench phagocytosis. Interestingly,"Don't Eat Me" signal (DEMs) blockade with anti-CD47 monoclonal Antibody (mAb) showed promising activity in pretreated NHL,through increase of phagocytosis by TAM.CD24 was also demonstrated to be involved in DEMs in solid cancer.As a matter of fact, tumor-expressed CD24 promotes immune evasion through its interaction with the inhibitory receptor sialic-acid-binding Ig-like lectin10 (Siglec-10),expressed by TAM with immunosuppressive phenotype (M2-like).In a preclinical model of CD24+ solid tumors (ovarian and breast cancer) the blockade of CD24-Siglec-10 interaction with anti-CD24 mAb showed improvement of TAM-associated phagocytosis in vitro and TAM-dependent reduction of tumor growth and increase of survival in vivo.It is worth mentioning that CD24 can be expressed in some phases of B-cell differentiation and both MCL and CLL derives from a B-cell precursor with upregulated CD24.In this setting,CD24 might play a critical role in the anti-phagocytic signal, since MCL and CLL represents a subset of B-cell malignancies with a considerable hostile TME with M2-like TAM,able to jeopardize anti-cancer immunity.Therefore, the possibility to boost innate anti-cancer immunity through this DEMs blockade could provide new therapeutic options to previous heavily pretreated relapsed/refractory MCL and CLL patients.

MCL is an aggressive B-NHL with dismal prognosis with high probability of relapse after conventional immunochemotherapeutic regimen. CLL is instead an incurable chronic B-cell malignancy with higher probability of relapse after several lines of conventional therapies and a non-negligible risk of progression into an aggressive lymphoma. Further approaches are needed to provide valid alternatives for these relapsed and refractory diseases. In these two settings, TME is known to be involved in cancer cell survival and confers a negative impact on standard treatment efficacy and adoptive T cell immunity, for which new immunotherapeutic agents could be an alternative approach in case of poor prognostic settings. Within TME, TAM are involved in improving tumor growth survival in MCL and CLL, dampening immunotherapy as well. Anti-CD47 mAb turned out to be a consistent DEMs that, once blocked, is able to improve phagocytosis and clearance of tumor cells in blood cancer. CD24 has been recently validated as another DEMs in preclinical analysis in solid cancer. Since CD24 is expressed during early phase of B-cell differentiation, MCL and CLL might take advantage of the blockade of this signal, since TAM and NCLs are strictly interconnected with their corresponding tumoral cells, providing tumor cell proliferation and immune escape.

To fulfill the purposes of this project, collection of leftover patient-derived samples will be routinary performed at the time of diagnosis and at the time of relapse of the disease, in this latter case with the aim to check any CD24, CD47 and CD20 surface expression modification on B-cell blasts (e.g., clone selection with CD24/CD47 upregulation after conventional regimen), SIRP-α and Siglec-10 expression on patient-derived Monocyte/Macrophage system (expressing higher levels of DEMs ligands as potential mechanism of resistance after conventional therapy).

Furthermore, phagocytosis assays with samples obtained at the time of relapse will be compared with the equivalent experiments performed with the samples collected at the time of diagnosis to evaluate any potential differences.

As previously described, phagocytosis analysis will be based on a co-culture process that involves the use of the anti-CD24 antibody (alone or in combination with other antibodies described in the secondary endpoint) incubating with macrophages (from healthy donor or from patient) and patient tumor cells (MCL or CLL), this latter labeled with a fluorescent substance (i.e., CFSE). Macrophage staining (with anti-CD11b-PE antibody) and subsequent flow cytometric analysis will be performed: the ratio between double stained macrophages (CD11b-PE+/CFSE+) and single stained macrophages (CD11b-PE+) will provide the entity of phagocytosis, which will be compared with the negative control and the other experimental conditions (antibody combinations described later in the secondary endpoints). The double staining of macrophages provides indirect results of phagocytosis (if the macrophage phagocytes CFSE+ cells, it will also acquire this staining in addition to that due to the anti-CD11b-PE antibody).

Finally, donor-derived macrophages will be isolated from PBMC obtained from leftover peripheral blood which remained within the circuit used for plateletpheresis of healthy donors. As a matter of fact, residual blood (almost 15 ml) can be found in the reservoir of this circuit that is normally trashed after the procedure. Donors will sign informed consent for use of leftover material for research purposes and this project in particular.

"Don't Eat me" Signal in Hematological Malignancies: CD24 as New Target to Improve Anti-cancer Immunity.

Rate of phagocytosis of human M2-like macrophages co-cultured with MCL and CLL blast cells treated with anti-CD24 mAb.

* Rate of phagocytosis with patient-derived monocytes system and autologous MCL/CLL blast cells with anti-CD24 mAb.
* Rate of phagocytosis with different mAb combinations and statistical comparison (anti-CD24, anti-CD47, anti-CD20, anti-CD24+anti-CD47, anti-CD47+anti-CD20, anti-CD24+anti-CD20, anti-CD47+anti-CD24+anti-CD20 mAbs) for donor-derived and patient-derived human macrophages co-cultured with human MCL and CLL blast cells derived from patients.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Idelalisib Post Allogeneic Hematopoietic Stem Cell Transplant (HSCT) in B Cell Derived Malignancies	NCT03151057	B Cells-Tumors B Cell Chronic ... Follicular Lymp... Mantle Cell Lym... Large B-Cell Di...	Idelalisib 100 ... Placebo Oral Ta...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Tolerance and Resistance to Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL	NCT03502876	B Cell Chronic ...		18 Years -	French Innovative Leukemia Organisation
Idelalisib Post Allogeneic Hematopoietic Stem Cell Transplant (HSCT) in B Cell Derived Malignancies	NCT03151057	B Cells-Tumors B Cell Chronic ... Follicular Lymp... Mantle Cell Lym... Large B-Cell Di...	Idelalisib 100 ... Placebo Oral Ta...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Efficacy/Safety of Frontline Alemtuzumab (Campath, MabCampath) vs Chlorambucil in Patients With Progressive B-Cell Lymphocytic Leukemia	NCT00046683	B Cell Chronic ...	alemtuzumab	18 Years -	Sanofi
"Don't Eat me" Signal in Hematological Malignancies: CD24 as New Target to Improve Anti-cancer Immunity.	NCT05888701	Mantle-cell Lym... B Cell Chronic ...		18 Years -	University of Milano Bicocca
"Don't Eat me" Signal in Hematological Malignancies: CD24 as New Target to Improve Anti-cancer Immunity.	NCT05888701	Mantle-cell Lym... B Cell Chronic ...		18 Years -	University of Milano Bicocca
Efficacy/Safety of Frontline Alemtuzumab (Campath, MabCampath) vs Chlorambucil in Patients With Progressive B-Cell Lymphocytic Leukemia	NCT00046683	B Cell Chronic ...	alemtuzumab	18 Years -	Sanofi
"Don't Eat me" Signal in Hematological Malignancies: CD24 as New Target to Improve Anti-cancer Immunity.	NCT05888701	Mantle-cell Lym... B Cell Chronic ...		18 Years -	University of Milano Bicocca

Spots Global Cancer Trial Database for b cell chronic lymphocytic leukemia