Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Vincristine

Dexamethasone acetate

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Tubulin Modulators

Antimitotic Agents

Monotherapy Lead-In (Day -7 to Day -1): Entospletinib (ENTO) 200 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 200 mg twice daily continuously in combination with vincristine (VCR) 0.5 mg intravenously (IV) on Days 1, 8, 15, and 22 of each cycle; dexamethasone (DEX) 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and central nervous system (CNS) prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a complete remission (CR) received stem cell transplant (SCT) (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a partial response \[PR\]) after induction were offered maintenance therapy with ENTO 200 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.

Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 0.5 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.

Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 1.0 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 1.0 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.

Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 2.0 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 2.0 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.

Entospletinib

CNS Prophylaxis

Gilead Study Director

The primary objective of this study is to evaluate the safety of entospletinib in combination with vincristine (VCR), and dexamethasone (DEX) in adults with previously treated relapsed or refractory B-cell lineage acute lymphoblastic leukemia (ALL).

This is a dose escalation study in which after 2 induction cycles participants may be put on maintenance for up to 36 cycles if they have obtained clinical benefit from the treatment.

Safety and Efficacy of Entospletinib With Vincristine and Dexamethasone in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

A Phase 1b/2, Open-Label, Dose Escalation and Expansion Study Evaluating the Safety and Efficacy of Entospletinib (GS-9973) With Vincristine and Dexamethasone in Adult Subjects With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

The occurrence of any of the following toxicities during Lead-in/Cycle 1 (Day -7 through Day 28) was considered a DLT if judged by the investigator to be possibly, probably, or definitely related to the administration of any drug in the treatment regimen (ENTO, VCR, DEX, institutional standard CNS prophylaxis):

* Grade 4 (or higher) non-hematologic toxicity
* Grade 3 non-hematologic toxicity lasting ≥ 7 days despite optimal supportive care
* Any Grade 3 non-hematologic laboratory value if:

  * Medical intervention was required to treat, or
  * The abnormality led to hospitalization, or
  * The abnormality persisted for \> 1 week
* Grade 4 Neutropenia (absolute neutrophil count \[ANC\] \< 500 /μL) persistent for greater than 14 days or associated with febrile neutropenia
* Grade 4 thrombocytopenia (platelets \< 25,000/μL) persisting for greater than 14 days (or greater than 25,000 /μL, but requiring prophylactic platelet transfusion to maintain this level)

Assessment of clinical response was made according to National Comprehensive Cancer Network (NCCN) guidelines on acute lymphoblastic leukemia (ALL) Version 2, 2016. CR required all of the following:

* No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement).
* Trilineage hematopoiesis (TLH) and \< 5% blasts in bone marrow aspirate.
* ANC \> 1000/μL.
* Platelets \> 100,000/μL.

Assessment of clinical response was made according to NCCN guidelines on ALL Version 2, 2016. Overall remission included CR and complete remission with incomplete hematologic recovery (CRi). CR required all of the following:

* No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement).
* TLH and \< 5% blasts in bone marrow aspirate.
* ANC \> 1000/μL.
* Platelets \> 100,000/μL.

CRi required all criteria for CR except platelet count and/or ANC:

* Platelets ≤ 100,000/μL and/or ANC is ≤ 1000/μL

PR required all of the following:

* No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement).
* TLH and bone marrow may contain ≥ 5% but less than 25% blast morphology.
* ANC \> 1000/μL.
* Platelets \> 100,000/μL.

Overall response included CR, CRi, and PR. CR required all of the following:

* No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement).
* TLH and \< 5% blasts in bone marrow aspirate.
* ANC \> 1000/μL.
* Platelets \> 100,000/μL.

CRi required all criteria for CR except platelet count and/or ANC:

* Platelets ≤ 100,000/μL and/or ANC is ≤ 1000/μL

PR required all criteria for CR except for bone marrow blasts:

* bone marrow may contain ≥ 5% but less than 25% blast morphology

Gilead Sciences

The Safety Analysis Set included all participants who received at least 1 dose of study treatment.

Monotherapy Lead-In (Day -7 to Day -1): ENTO 200 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 200 mg twice daily continuously in combination with VCR 0.5 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 200 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.

ENTO 200 mg + VCR 0.5 mg

ENTO 400 mg + VCR 0.5 mg

ENTO 400 mg + VCR 1.0 mg

ENTO 400 mg + VCR 2.0 mg

Total

Participants in Full Analysis Set (all participants who received at least 1 dose of study treatment) were analyzed.

Age, Continuous

Participants in Full Analysis Set were analyzed.

Sex: Female, Male

Race

Race/Ethnicity, Customized

Ethnicity

Canada

United States

Germany

Region of Enrollment

All Enrolled Analysis Set included all participants who received a study identification number in the study after screening.

Due to the low response rate observed with ENTO + VCR + DEX in adults with relapsed or refractory B-ALL, the sponsor decided not to proceed with Phase 2 (dose-expansion) and the cohort was subsequently closed with no participant enrolled.

Gilead Clinical Study Information Center

DLT Analysis Set included all participant in the Safety Analysis Set (all participants who received at least 1 dose of study treatment) who met at least one of the following criteria: received at least 21 days of ENTO, \> 50% of planned total dose of VCR and DEX, or experienced a DLT during the DLT assessment window.

Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)

The Full Analysis Set included all participants who received at least 1 dose of study treatment.

Percentage of Participants With Complete Remission (CR) at the End of Induction

Participants in the Full Analysis Set were analyzed.

Percentage of Participants With Overall Remission at the End of Induction

Percentage of Participants With Partial Response (PR) at the End of Induction

Percentage of Participants With Overall Response at the End of Induction

Overall Study

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Antirheumatic Agents

Etoposide

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Prednisone

Rituximab

Etoposide phosphate

rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone

R-CHOEP

dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab

DA-EPOCH-R

Laura K Hakala

Judit Joergensen, MD, PhD

Judit Joergensen

Peter Brown, MD, PhD

Peter Brown

Danny Stoltenberg, MD, PhD

Danny Stoltenberg

Thomas Stauffer Larsen, MD, PhD

Thomas Stauffer Larsen

Christian Bjorn Poulsen, MD, PhD

Christian Bjorn Poulsen

Sirpa Leppä, prof

Kaija Vasala, MD, PhD

Kaija Vasala

Annikki Aromaa-Häyhä, MD, PhD

Annikki Aromaa-Häyhä

Kaisa Sunela, MD, PhD

Kaisa Sunela

Sirkku Jyrkkiö, MD, PhD

Sirkku Jyrkkiö

Oystein Fluge, MD, PhD

Oystein Fluge

Harald Holte, MD, PhD

Harald Holte

Peter Meyer, MD, PhD

Peter Meyer

Martin Maisenhölder, Md, PhD

Martin Maisenhölder

Unn Merete Fagerli, MD, PhD

Unn Merete Fagerli

Kristina Drott, MD, PhD

Kristina Drott

Sirpa Leppa, prof

This study is testing whether stratification of the patients according to biological risk factors for different treatment groups will improve the outcome of patients with clinically high diffuse large B-cell lymphoma (DLBCL).

For young clinically high-risk diffuse large B-cell lymphoma (DLBCL) patients the optimal therapy has not been established. Previous Nordic phase II studies, where dose-dense chemoimmunotherapy (R-CHOEP-14) with systemic CNS prophylaxis (HD-Mtx and HD-AraC) was given, demonstrated favorable outcome in comparison to historical controls. However, the patients with biological risk factors, such as translocation of bcl2 and myc oncogenes or and/or high BCL2 and MYC expression or deletion 17p and/or high P53 expression had significantly higher risk of death, as compared to patients without aberrations. The figures provide evidence for an unmet clinical need for the patients with biological risk factors, and underscore the importance of a clinical trial, where both biological and clinical risk factors play a role in the treatment planning.

In this trial treatment intensity varies according to presence or absence of biological risk factors. All patients receive a prephase medication consisting of prednisone and vincristine and two cycles of R-CHOP and high dose (HD) methotrexate. Subsequently, depending on the biological risk factors either four additional cycles of R-CHOEP (standard arm with no risk factors) or four dose adjusted R-EPOCH courses (experimental arm with risk factors) are given, followed by one course of high dose cytarabine (Ara-C) and R. R-CHOEP courses should be given with a two-week and R-EPOCH with a three-week interval.

Stratification into group A (standard) or group B (experimental) based on biological risk factors

Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis

Biomarker Driven and Dose Intensified Chemoimmunotherapy With Early CNS Prophylaxis in Patients Less Than 65 Years With High Risk Diffuse Large B-Cell Lymphoma

individual deidentified participant data (including data dictionaries) will be shared

Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first. Otherwise, patients will be censored at the last date they were known to be alive. For patients not responding at any time point on study treatment, TTF is defined as one day.

Number of patients with treatment-related adverse events graded according to the NCI CTCAE v 4.03

Number of patients with complete or partial response

Identification of genomic aberrations (for example mutations and translocations), gene expression profiles and protein expression from the tumor tissue and circulation that predict clinical course of the disease

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety and Efficacy of Entospletinib With Vincristine and Dexamethasone in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)	NCT02404220	Acute Lymphobla...	Entospletinib Vincristine Dexamethasone CNS Prophylaxis	18 Years -	Gilead Sciences
Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis	NCT03293173	Lymphoma, Large...	R-CHOEP DA-EPOCH-R	18 Years - 64 Years	Nordic Lymphoma Group

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