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

• Sponsor: Curis, Inc. (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03328078
• Collaborator: (none)
• Enrollment: 181
• Locations: 10
• Arms: 3
• Anticipated Duration (Months): 88.1
• Patients Per Site: 18.1
• Patients Per Site Per Month: 0.2

Study Details

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), 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

Study Design

• Study Type: Interventional
• Anticipated 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 ibrutinibPart 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: Dec 28, 2017
• Anticipated Primary Completion Date: Nov 1, 2023
• Anticipated Study Completion Date: May 1, 2025

Arms and Interventions

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 Names: 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 Names: 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 Names: CA-4948 ; Drug: ibrutinib; 560 mg QD of oral ibrutinib (or 420 mg QD for WM/LPL and CLL/SLL)

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) [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) [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 [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. [24- 36 months]

   Assessed by CR

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

   Assessed by ORR

Secondary Outcome Measures

1. Pharmacokinetic (PK) profile of emavusertib measured by AUC [24- 36 months]

   Area Under the concentration-time curve (AUC)

2. Pharmacokinetic (PK) profile of emavusertib measured by Cmax [24- 36 months]

   Maximum plasma concentration (Cmax)

3. Pharmacokinetic (PK) profile of emavusertib measured by Tmax [24- 36 months]

   Time to maximum plasma concentration (Tmax)

4. Pharmacokinetic (PK) profile of emavusertib measured by plasma terminal half-life [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) [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) [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) [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) [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) [24 - 36 months]

   Assessed by OS

10. Part B: To estimate the blood-brain barrier penetration in CNS lymphoma patients [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

5. 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

6. Inhaled, intranasal, intraarticular and topical steroids are permitted

7. Use of any investigational agent within 21 days or 5 half-lives, whichever is shorter, prior to start of study treatment

8. 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

9. 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

10. B-cell NHL of the following subtypes:

11. Burkitt lymphoma

12. Lymphoblastic lymphoma or leukemia

13. Post-transplantation lymphoproliferative disorder

14. Known primary mediastinal, ocular, or epidural, DLBCL

15. WM patients requiring urgent treatment due to hyperviscosity

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Phoenix	Arizona	United States	85054
2	Smilow Cancer Hospital at Yale-New Haven	New Haven	Connecticut	United States	06510
3	Mayo Clinic	Jacksonville	Florida	United States	32224
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Fred and Pamela Buffett Cancer Center	Omaha	Nebraska	United States	68198
6	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
7	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
8	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
9	University of Tennessee Medical Center	Knoxville	Tennessee	United States	37920
10	Swedish Cancer Institute	Seattle	Washington	United States	98104

Sponsors and Collaborators

• Curis, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Curis, Inc.
• ClinicalTrials.gov Identifier: NCT03328078
• Other Study ID Numbers: CA-4948-101
• First Posted: Nov 1, 2017
• Last Update Posted: Apr 7, 2022
• Last Verified: Apr 1, 2022

• 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: Neoplasms; Hematologic Neoplasms

Study Results

No Results Posted as of Apr 7, 2022