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A Study of CA-4948 in Patients With Relapsed or Refractory Hematologic Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03328078
Recruitment Status : Active, not recruiting
First Posted : November 1, 2017
Last Update Posted : April 7, 2022
Sponsor:
Information provided by (Responsible Party):
Curis, Inc.

Brief Summary:

This is a multi-center, open-label trial to evaluate oral administration of emavusertib (CA-4948) in adult patients with relapsed/refractory hematologic malignancies. Part A will evaluate escalating doses of emavusertib either as monotherapy (Part A1) or in combination with ibrutinib for non- Hodgkin's Lymphoma (NHL), Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (Part A2). Once the combination dose has been determined, Part B will comprise an expansion phase to assess efficacy (CR rate or ORR) and safety of the RP2D of emavusertib and ibrutinib in 4 Non-Hodgkin Lymphoma (NHL) disease-specific cohorts:

  • Cohort 1 - Marginal zone lymphoma (MZL)
  • Cohort 2 - activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) or extranodal subtypes: Leg-, testicular-, or not otherwise specified (NOS)-type
  • Cohort 3 - Primary central nervous system lymphoma (PCNSL)
  • Cohort 4 - Patients receiving ibrutinib monotherapy who have developed adaptive, secondary resistance. Indications include:

    • Mantle Cell Lymphoma (MCL), MZL, CLL/SLL, or WM/LPL
    • Indications for which ibrutinib is National Comprehensive Cancer Network (NCCN)-listed (e.g., PCNSL)
    • Patients with NHL and known myddosome mutations
    • Patients may be candidates for maintaining ibrutinib while emavusertib will be added for resistance reversal. A brief gap of ibrutinib therapy of <3 weeks is acceptable.

Condition or disease Intervention/treatment Phase
Relapsed Hematologic Malignancy Refractory Hematologic Malignancy Drug: Emavusertib Drug: ibrutinib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 181 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Part A will evaluate escalating doses of emavusertib (CA-4948) either as monotherapy (Part A1) or in combination with ibrutinib (Part A2). Once the combination dose has been determined, Part B will comprise an expansion phase to assess efficacy and safety of the recommended Phase 2 dose (RP2D) of emavusertib and ibrutinib
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: TakeAim Lymphoma: An Open-Label, Dose Escalation and Dose Expansion Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients With Relapsed or Refractory Hematologic Malignancies
Actual Study Start Date : December 28, 2017
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : May 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Ibrutinib

Arm Intervention/treatment
Experimental: Emavusertib (CA-4948) dose escalation
Part A1: Dose-level cohorts with up to 6 patients each will be used to define the Maximum Tolerated Dose (MTD) for emavusertib .
Drug: Emavusertib
Emavusertib (formulated for oral administration for QD or BID dosing)
Other Name: CA-4948

Experimental: Emavusertib (CA-4948) and ibrutinib dose escalation
Part A2: Evaluate escalating dose levels of oral emavusertib in combination with 560 mg daily (QD) of oral ibrutinib (or 420 mg QD for WM/LPL and CLL/SLL). Separate escalation of emavusertib will be performed for each of these ibrutinib doses. The starting dose of emavusertib to be used in combination will be 200 mg twice a day (BID). It is anticipated that 12 to 18 patients will be required to establish optimal combination dosing.
Drug: Emavusertib
Emavusertib (formulated for oral administration for QD or BID dosing)
Other Name: CA-4948

Drug: ibrutinib
560 mg QD of oral ibrutinib (or 420 mg QD for WM/LPL and CLL/SLL)

Experimental: Emavusertib (CA-4948) and ibrutinib dose expansion

In expansion phase, the emavusertib recommended Phase 2 dose (RP2D) in combination with ibrutinib will be administered in Non-Hodgkin Lymphoma (NHL) disease-specific cohorts. Approximately 131 NHL patients will be enrolled in 4 NHL disease specific cohorts:

  • Cohort 1 - Marginal zone lymphoma (MZL)
  • Cohort 2 - ABC diffuse large B-cell lymphoma (DLBCL) or extranodal subtypes: Leg-, testicular-, or NOS-type
  • Cohort 3 - Primary central nervous system lymphoma (PCNSL)
  • Cohort 4 - Patients receiving ibrutinib monotherapy who have developed adaptive, secondary resistance. Indications include:

    • Mantle Cell Lymphoma (MCL), MZL, CLL/SLL, or WM/LPL
    • Indications for which ibrutinib is National Comprehensive Cancer Network (NCCN)-listed (e.g., PCNSL)
    • Patients with NHL and known myddosome mutations
    • Patients may be candidates for maintaining ibrutinib while emavusertib will be added for resistance reversal. A brief gap of ibrutinib therapy of <3 weeks is acceptable.
Drug: Emavusertib
Emavusertib (formulated for oral administration for QD or BID dosing)
Other Name: CA-4948

Drug: ibrutinib
560 mg QD of oral ibrutinib (or 420 mg QD for WM/LPL and CLL/SLL)




Primary Outcome Measures :
  1. Part A: To determine the safety and tolerability of emavusertib as a monotherapy and in combination with ibrutinib: dose-limiting toxicity (DLT) [ Time Frame: 12 months ]
    The number of patients with a dose-limiting toxicity (DLT) in the first treatment cycle

  2. Part A: Maximum tolerated dose (MTD) of emavusertib as a monotherapy and in combination with ibrutinib measured by dose-limiting toxicities (DLTs) [ Time Frame: 12 months ]
    MTD determined by the highest dose level studied at which fewer than 2 out of 6 subjects (<33%) experience a dose limiting toxicity

  3. Part A: Recommended Phase 2 Dose (RP2D) of emavusertib as a monotherapy and in combination with ibrutinib based on overall tolerability data [ Time Frame: 12 months ]
    RP2D selected based on overall tolerability data from all patients treated at different dose levels and will not exceed the MTD.

  4. Part B: To assess complete response (CR) rate of emavusertib in combination with ibrutinib. [ Time Frame: 24- 36 months ]
    Assessed by CR

  5. Part B: To assess overall response rate (ORR) of emavusertib in combination with ibrutinib. [ Time Frame: 24- 36 months ]
    Assessed by ORR


Secondary Outcome Measures :
  1. Pharmacokinetic (PK) profile of emavusertib measured by AUC [ Time Frame: 24- 36 months ]
    Area Under the concentration-time curve (AUC)

  2. Pharmacokinetic (PK) profile of emavusertib measured by Cmax [ Time Frame: 24- 36 months ]
    Maximum plasma concentration (Cmax)

  3. Pharmacokinetic (PK) profile of emavusertib measured by Tmax [ Time Frame: 24- 36 months ]
    Time to maximum plasma concentration (Tmax)

  4. Pharmacokinetic (PK) profile of emavusertib measured by plasma terminal half-life [ Time Frame: 24- 36 months ]
    Plasma terminal elimination half-life (T 1/2)

  5. To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by overall response rate (ORR) [ Time Frame: 24- 36 months ]
    Assessed by ORR

  6. To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by duration of response (DOR) [ Time Frame: 24- 36 months ]
    Assessed by DOR

  7. To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by disease control rate (DCR) [ Time Frame: 24- 36 months ]
    Assessed by DCR

  8. To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by progression free survival (PFS) [ Time Frame: 24- 36 months ]
    Assessed by PFS

  9. To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by overall survival (OS) [ Time Frame: 24 - 36 months ]
    Assessed by OS

  10. Part B: To estimate the blood-brain barrier penetration in CNS lymphoma patients [ Time Frame: 1 day ]
    CNS liquor with be sampled from an Ommaya reservoir or with a spinal puncture about 3 hours after oral dosing of emavusertib. At approximately the same timepoint, a peripheral blood sample will be taken to obtain a plasma sample. The respective emavusertib concentrations will be measured in the liquor and in plasma samples. The liquor vs plasma concentration ratio will provide a rough estimate of the blood-brain barrier (BBB) penetration of emavusertib following oral dosing.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females greater than or equal to 18 years of age
  2. Life expectancy of at least 3 months
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
  4. For Part A1: Diagnosis of histopathologically confirmed B-cell hematological malignancy (as per the World Health Organization [WHO] 2016 classification; Swedow 2016); eligible subtypes include follicular lymphoma, MZL, DLBCL, mantle cell lymphoma, and WM/LPL without the urgent need for treatment hyperviscosity.

For Part A2: Diagnosis of histopathologically confirmed B-cell NHL, as per the WHO 2016 classification (Swerdlow et al. 2016). Eligible NHL subtypes include follicular lymphoma, MZL, mantle cell lymphoma, DLBCL(including extranodal lymphomas of leg-, testicular-, or NOS type), CLL/SLL, primary or secondary CNS lymphoma and WM/LPL.

For Part B: Diagnosis of histopathologically confirmed B-cell NHLs, including applicable confirmation as per the WHO 2016 classification (Swerdlow et al. 2016):

  • Cohort 1: Marginal zone lymphoma
  • Cohort 2: ABC-DLBCL, or extranodal subtypes: Leg-, testicular-, or NOS-type. The population will be enriched for MYD88 L265P mutations. As this occurs more frequently in the ABC-DLBCL(activated B-cell (Hans et al. 2004) subtype, all patients with this subtype qualify for enrollment. If the MYD88 mutation status is unknown at baseline, the lymphoma will be tested for MYD88 mutations.
  • Cohort 3: Primary CNS Lymphoma (PCNSL) only. If the MYD88 mutation status is unknown at baseline, the lymphoma will be tested for MYD88 mutations.
  • Cohort 4: Patients receiving ibrutinib monotherapy who have developed adaptive, secondary resistance. Indications include:

    • MCL, MZL, CLL/SLL, or WM/LPL
    • Indications for which ibrutinib is NCCN-listed (e.g., PCNSL)
    • Patients with NHL and known myddosome mutations
    • Patients may be candidates for maintaining ibrutinib while emavusertib will be added for resistance reversal. A brief gap of ibrutinib therapy of <3 weeks is acceptable.

Exclusion Criteria:

  1. Patient with active central nervous system (CNS) involvement other than PCNSL at study entry are ineligible.
  2. Radiotherapy delivered to non-target lesions involving >25% of bone marrow within one week prior to starting study treatment or delivered to target lesions that will be followed on the study (NOTE: prior sites of radiation will be recorded)
  3. Any prior anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to start of study treatment (with the exception of ibrutinib for Parts A2 and B, which may be continued as part of this study without interruption)
  4. Current or planned glucocorticoid therapy, with the following exceptions:

    1. Doses ≤ 10 mg/day prednisolone or equivalent is allowed, provided that the steroid dose has been stable or tapering for at least 14 days prior to the first dose of study treatment
    2. Inhaled, intranasal, intraarticular and topical steroids are permitted
  5. Use of any investigational agent within 21 days or 5 half-lives, whichever is shorter, prior to start of study treatment
  6. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia, that has not resolved to Grade ≤ 1 within 7 days prior to start of study treatment unless approved by the Medical Monitor
  7. Known allergy or hypersensitivity to any component of the formulation of emavusertib (or ibrutinib for entry into Parts A2 or B) used in this study
  8. B-cell NHL of the following subtypes:

    1. Burkitt lymphoma
    2. Lymphoblastic lymphoma or leukemia
    3. Post-transplantation lymphoproliferative disorder
    4. Known primary mediastinal, ocular, or epidural, DLBCL
    5. WM patients requiring urgent treatment due to hyperviscosity

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03328078


Locations
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United States, Arizona
Mayo Clinic
Phoenix, Arizona, United States, 85054
United States, Connecticut
Smilow Cancer Hospital at Yale-New Haven
New Haven, Connecticut, United States, 06510
United States, Florida
Mayo Clinic
Jacksonville, Florida, United States, 32224
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Nebraska
Fred and Pamela Buffett Cancer Center
Omaha, Nebraska, United States, 68198
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
University of Tennessee Medical Center
Knoxville, Tennessee, United States, 37920
United States, Washington
Swedish Cancer Institute
Seattle, Washington, United States, 98104
Sponsors and Collaborators
Curis, Inc.
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Responsible Party: Curis, Inc.
ClinicalTrials.gov Identifier: NCT03328078    
Other Study ID Numbers: CA-4948-101
First Posted: November 1, 2017    Key Record Dates
Last Update Posted: April 7, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Curis, Inc.:
DLBCL
MCL
WM
LPL
MYD88
IRAK4
NHL
AML
CLL
SLL
MZL
PCNSL
Additional relevant MeSH terms:
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Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Hematologic Diseases