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

Heart and Blood Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Plasmacytoma

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Janus Kinase Inhibitors

Proteasome Inhibitors

Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg ruxolitinib, Cohort 3) 15mg ruxolitinib

Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen

Carfilzomib

Ruxolitinib

Shebli Atrash, MD

The primary objective of Phase I is to establish the maximum tolerated dose (MTD) of ruxolitinib in combination with carfilzomib and dexamethasone. The primary objective of phase II is to evaluate progression-free survival (PFS) at 4 months in multiple myeloma subjects who receive the combination treatment carfilzomib, dexamethasone, and ruxolitinib.

This is an open-label, Phase I/II study of carfilzomib, ruxolitinib, and low-dose dexamethasone for carfilzomib-refractory multiple myeloma. Phase I is designed to evaluate overall maximum tolerated dose (MTD) of ruxolitinib in combination with carfilzomib and dexamethasone in the following cohorts: Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg ruxolitinib, Cohort 3) 15mg ruxolitinib. Phase II is designed to evaluate 4-month progression-free survival (PFS) in the following cohorts: Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen. Up to 18 evaluable subjects will be enrolled in Phase I over approximately 12 months. An additional 30 evaluable subjects will be enrolled in Phase II over 24 months.

LCI-HEM-MYE-CRD-004 (MMRC-073 CARJAK): Study of CRD for Carfilzomib-Refractory Multiple Myeloma

LCI-HEM-MYE-CRD-004 (MMRC-073 CARJAK): Phase I/II Study of Carfilzomib, Ruxolitinib, and Low Dose Dexamethasone for Carfilzomib-Refractory Multiple Myeloma

DLTs will be determined for each subject as a binary variable indicating whether or not the subject experienced a DLT during Cycle 1

Objective response will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of PR or better as per the IMWG criteria

Clinical benefit will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of minimal response (MR) or better as determined by the IMWG criteria

Disease control will be determined for each subject as a binary variable indicating whether or not the subject achieved a disease response or stable disease for greater than or equal to 8 weeks

PFS is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death without progressive disease.

Time to best response will be defined as the time from initiation of ruxolitinib treatment to the time of best objective status assessment of response.

Overall survival is defined as the duration from initiation of ruxolitinib treatment to the date of death from any cause.

Time to progression (TTP) is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death.

Duration of response will be defined as the time from first objective status assessment of response to the time of first documented disease progression or death.

Incyte Corporation

Multiple Myeloma Research Consortium

Amgen

Wake Forest University Health Sciences

Cohort 1) 5mg ruxolitinib

Carfilzomib: Irreversible proteasome inhibitor

Ruxolitinib: Oral JAK inhibitor

Dexamethasone: glucocorticoid

Phase I 5 mg Ruxolitinib

Cohort 2) 10mg ruxolitinib

Carfilzomib: Irreversible proteasome inhibitor

Ruxolitinib: Oral JAK inhibitor

Dexamethasone: glucocorticoid

Phase I 10 mg Ruxolitinib

Cohort 3) 15mg ruxolitinib

Carfilzomib: Irreversible proteasome inhibitor

Ruxolitinib: Oral JAK inhibitor

Dexamethasone: glucocorticoid

Phase I 15 mg Ruxolitinib

Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen

Carfilzomib: Irreversible proteasome inhibitor

Ruxolitinib: Oral JAK inhibitor

Dexamethasone: glucocorticoid

Phase II

Phase I 5mg Ruxolitinib

Phase I 10mg Ruxolitinib

Phase I 15 mg Ruxolitibin

Note: the sum of the number of participants who started in the Age subgroups add up to the total number of participants who started for each of the respective ruxolitinib dose levels.

Age, Categorical

Note: the sum of the number of participants who started in the Sex subgroups add up to the total number of participants who started for each of the respective ruxolitinib dose levels.

Note: the sum of the number of participants who started in the Ethnicity subgroups add up to the total number of participants who started for each of the respective ruxolitinib dose levels.

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Note: the sum of the number of participants who started in the Region subgroups add up to the total number of participants who started for each of the respective ruxolitinib dose levels.

The Phase II part of the trial did not open to enrollment. The MTD was not identified in the Phase I part of the trial.

Jim Symanowski, PhD

Dose Limiting Toxicity (DLT)

Participants who initiate protocol-directed therapy and have measurable disease at baseline.

Objective Response Rate (ORR)

Phase I 5m Ruxolitinib

Clinical Benefit Rate

Number of participants who achieved a disease response of stables disease or better and maintained the response for at least 8 weeks.

Disease Control Rate

Phase I 15mg Ruxolitinib

All participants who initiate study treatment.

Progression-free Survival (PFS)

Time to best response calculated only for participants who achieved a PR or better.

Time to Best Response

Overall Survival

Time to Progression

Duration of best response calculated only for participants who achieved a PR or better.

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
LCI-HEM-MYE-CRD-004 (MMRC-073 CARJAK): Study of CRD for Carfilzomib-Refractory Multiple Myeloma	NCT03773107	Multiple Myelom...	Carfilzomib Ruxolitinib Dexamethasone	18 Years - 75 Years	Wake Forest University Health Sciences

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