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

• ClinicalTrials.gov Identifier: NCT03328078
• Recruitment Status: Recruiting
• First Posted: November 1, 2017
• Last Update Posted: February 2, 2023
• Sponsor: Curis, Inc.
• Information provided by (Responsible Party): Curis, Inc.

Study Description

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) (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
  • 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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 221 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: August 2026
• Estimated Study Completion Date: August 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Emavusertib (CA-4948) dose escalation; Part A1: Dose-level cohorts with up to approximately 6 patients each will be used to define the Maximum Tolerated Dose (MTD) for emavusertib .	Drug: Emavusertib; Emavusertib (formulated for oral administration for 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. The starting dose of emavusertib to be used in combination will be 200 mg twice a day (BID). It is anticipated that 12 to 20 patients ata potential dose level will be required to establish optimal combination dosing.	Drug: Emavusertib; Emavusertib (formulated for oral administration for BID dosing); Other Name: CA-4948; Drug: ibrutinib; 560 mg QD of oral ibrutinib
Experimental: Emavusertib (CA-4948) and ibrutinib dose expansion; In the 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 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 BID dosing); Other Name: CA-4948; Drug: ibrutinib; 560 mg QD of oral ibrutinib

Outcome Measures

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 and ibrutinib measured by AUC [ Time Frame: 24- 36 months ]
   Area Under the concentration-time curve (AUC)
2. Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax [ Time Frame: 24- 36 months ]
   Maximum plasma concentration (Cmax)
3. Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin [ Time Frame: 24- 36 months ]
   Minimum plasma concentration (Cmin)
4. Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax [ Time Frame: 24- 36 months ]
   Time to maximum plasma concentration (Tmax)
5. Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life [ Time Frame: 24- 36 months ]
   Plasma terminal elimination half-life (T 1/2)
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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.

Eligibility Criteria

• 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), and primary or secondary CNS lymphoma.

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
  • 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 and LPL
   6. CLL/SLL

Contacts and Locations

Contacts

Contact: Reinhard von Roemeling, MD; 617-503-6500; clinicaltrials@curis.com

Locations

United States, Arizona

Mayo Clinic; Recruiting

Phoenix, Arizona, United States, 85054

United States, California

UCLA Department of Medicine - Hematology/Oncology; Recruiting

Santa Monica, California, United States, 90404

United States, Connecticut

Smilow Cancer Hospital at Yale-New Haven; Recruiting

New Haven, Connecticut, United States, 06510

United States, Florida

Mayo Clinic; Recruiting

Jacksonville, Florida, United States, 32224

United States, Minnesota

Mayo Clinic; Recruiting

Rochester, Minnesota, United States, 55905

United States, Nebraska

Fred and Pamela Buffett Cancer Center; Recruiting

Omaha, Nebraska, United States, 68198

United States, New Jersey

Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

United States, New York

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

United States, Pennsylvania

Hospital of the University of Pennsylvania; Active, not recruiting

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

University of Tennessee Medical Center; Recruiting

Knoxville, Tennessee, United States, 37920

United States, Washington

Swedish Cancer Institute; Active, not recruiting

Seattle, Washington, United States, 98104

Sponsors and Collaborators

Curis, Inc.

More Information

• Responsible Party: Curis, Inc.
• ClinicalTrials.gov Identifier: NCT03328078
• Other Study ID Numbers: CA-4948-101
• First Posted: November 1, 2017
• Last Update Posted: February 2, 2023
• Last Verified: February 2023

• 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; MYD88; IRAK4; NHL; AML; MZL; PCNSL

Additional relevant MeSH terms:

Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Hematologic Diseases