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

• Status: Recruiting
• Trial end date: 2022-12-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a multi-center, open-label trial to evaluate oral administration of CA-4948 in adult patients with relapsed/refractory hematologic malignancies. Part A will evaluate escalating doses of CA-4948 either as monotherapy (Part A1) or in combination with ibrutinib for non- Hodgkin's Lymphoma (NHL), 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) and safety of the RP2D of CA-4948 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 CA-4948 will be added for resistance reversal. A brief gap of ibrutinib therapy of <3 weeks is acceptable.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Curis, Inc.

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, lymphoplasmacytic 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 Waldenström macroglobulinemia / 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 CA-4948 will be added for resistance reversal. A brief gap of ibrutinib therapy of <3 weeks is acceptable.

5. Relapsed or refractory measurable disease for which patients are ineligible for or have exhausted standard therapeutic options that would be considered standard of care

Exclusion Criteria:

1. Active central nervous system (CNS) involvement other than PCNSL (Part A2 or B) or secondary CNS lymphoma (Part B only).

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 CA-4948 (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