Description:
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.
Title
- Brief Title: A Study of CA-4948 in Patients With Relapsed or Refractory Hematologic Malignancies
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
CA-4948-101
- NCT ID:
NCT03328078
Conditions
- Relapsed Hematologic Malignancy
- Refractory Hematologic Malignancy
Interventions
Drug | Synonyms | Arms |
---|
CA-4948 | | CA-4948 |
Purpose
This is a multi-center, open-label trial of orally administered CA-4948 monotherapy in adult
patients with Relapsed or Refractory Hematologic Malignancies. The trial will be conducted in
2 parts: an initial Dose Escalation Phase (Part A) of CA-4948 in patients with Relapsed or
Refractory Hematologic Malignancies, and a Dose Expansion Phase (Part B) of CA-4948 in
patients with selected RR hematologic malignancies (including NHL with and without myeloid
differentiation primary response 88 (MYD88) mutations, and AML).
Trial Arms
Name | Type | Description | Interventions |
---|
CA-4948 | Experimental | Part A: Dose-level cohorts with up to 6 patients each will be used to define the Maximum Tolerated Dose (MTD) for CA-4948.
Part B: The expansion phase of the study will be conducted in patients with Relapsed or Refractory Non-Hodgkin Lymphoma with and without MYD88 mutations and with Relapsed or Refractory Acute Myeloid Leukemia. Patients will be treated with CA-4948 at the Recommended Phase 2 Dose (RP2D) or the MTD (or highest dose tested if MTD is not reached). | |
Eligibility 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. Diagnosis of histopathologically confirmed hematologic malignancies. For NHL:
Confirmed B-cell NHL (as per the World Health Organization [WHO] 2016 classification
including WM/LPL). For AML: Diagnosis of histopathologically confirmed AML (as per the
World Health Organization [WHO] 2016 classification; Owen 2013) that is relapsed
and/or refractory.
5. Relapsed or refractory 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 of their malignancy.
2. Radiotherapy delivered to non-target lesions 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. History of allogeneic stem cell transplant for NHL
4. Any prior anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy,
etc., received within 14 days prior to start of CA-4948
5. 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 CA-4948
2. Inhaled, intranasal, intraarticular and topical steroids are permitted
6. Use of any investigational agent within 28 days or 5 half-lives, whichever is shorter,
prior to start of CA-4948
7. 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 CA-4948 unless approved by the Medical Monitor
8. Known allergy or hypersensitivity to any component of the formulation of CA-4948 used
in this study
9. Diagnosis of acute promyelocytic leukemia (APL, M3) for AML
10. Hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of CA-4948
for AML
11. Blast transformation of CML into AML
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | The number of patients with a dose-limiting toxicity (DLT) in the first treatment cycle |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Toxicity will be graded and recorded according to the NCI CTCAE v4.03. |
Secondary Outcome Measures
Measure: | Pharmacokinetic (PK) profile of CA-4948 measured by AUC |
Time Frame: | 24- 36 months |
Safety Issue: | |
Description: | Area Under the concentration-time curve (AUC) |
Measure: | Pharmacokinetic (PK) profile of CA-4948 measured by Cmax |
Time Frame: | 24- 36 months |
Safety Issue: | |
Description: | Maximum plasma concentration (Cmax) |
Measure: | Pharmacokinetic (PK) profile of CA-4948 measured by Cmin |
Time Frame: | 24- 36 months |
Safety Issue: | |
Description: | Trough plasma concentration (Cmin) |
Measure: | Pharmacokinetic (PK) profile of CA-4948 measured by Tmax |
Time Frame: | 24- 36 months |
Safety Issue: | |
Description: | Time to maximum plasma concentration (Tmax) |
Measure: | Pharmacokinetic (PK) profile of CA-4948 measured by plasma terminal half-life |
Time Frame: | 24- 36 months |
Safety Issue: | |
Description: | Plasma terminal elimination half-life (T 1/2) |
Measure: | Preliminary anti-cancer activity of oral CA-4948 in patients with RR NHL with and without MYD88 mutations and with RR AML |
Time Frame: | 24- 36 months |
Safety Issue: | |
Description: | Assessed by Revised Response Criteria for Malignant Lymphoma (for NHL), by the consensus panel recommendations from the Sixth International Workshop on WM (for WM) and by the 2003 Revised IWG Criteria for AML (for AML). |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Curis, Inc. |
Trial Keywords
- DLBCL
- MCL
- WM
- LPL
- MYD88
- IRAK4
- NHL
- AML
Last Updated
January 17, 2019