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

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ClinicalTrials.gov Identifier: NCT03328078
Recruitment Status : Recruiting
First Posted : November 1, 2017
Last Update Posted : August 27, 2020
Sponsor:
Information provided by (Responsible Party):
Curis, Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
Relapsed Hematologic Malignancy Refractory Hematologic Malignancy Drug: CA-4948 Drug: ibrutinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Part A will evaluate escalating doses of 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 CA-4948 and ibrutinib
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 28, 2017
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Ibrutinib

Arm Intervention/treatment
Experimental: 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 CA-4948.
Drug: CA-4948
CA-4948 (formulated for oral administration for QD or BID dosing)

Experimental: CA-4948 and ibrutinib dose escalation
Part A2: Evaluate escalating dose levels of oral CA-4948 in combination with 560 mg daily (QD) of oral ibrutinib (or 420 mg QD for WM/LPL and CLL/SLL). Separate escalation will be performed for each of these ibrutinib doses. The starting dose of CA-4948 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: CA-4948
CA-4948 (formulated for oral administration for QD or BID dosing)

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

Experimental: CA-4948 and ibrutinib dose expansion

In expansion phase, the CA-4948 recommended Phase 2 dose (RP2D) in combination with ibrutinib will be administered in Non-Hodgkin Lymphoma (NHL) disease-specific cohorts. Up to 46 NHL patients will be enrolled in each of the following 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 CA-4948 will be added for resistance reversal. A brief gap of ibrutinib therapy of <3 weeks is acceptable.
Drug: CA-4948
CA-4948 (formulated for oral administration for QD or BID dosing)

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




Primary Outcome Measures :
  1. To determine the safety and tolerability of CA-4948 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 CA-4948 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 CA-4948 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 CA-4948 in combination with ibrutinib. [ Time Frame: 24- 36 months ]
    Assessed by CR

  5. Part B: To assess overall response rate (ORR) of CA-4948 in combination with ibrutinib. [ Time Frame: 24- 36 months ]
    Assessed by ORR


Secondary Outcome Measures :
  1. Pharmacokinetic (PK) profile of CA-4948 measured by AUC [ Time Frame: 24- 36 months ]
    Area Under the concentration-time curve (AUC)

  2. Pharmacokinetic (PK) profile of CA-4948 measured by Cmax [ Time Frame: 24- 36 months ]
    Maximum plasma concentration (Cmax)

  3. Pharmacokinetic (PK) profile of CA-4948 measured by Cmin [ Time Frame: 24- 36 months ]
    Trough plasma concentration (Cmin)

  4. Pharmacokinetic (PK) profile of CA-4948 measured by Tmax [ Time Frame: 24- 36 months ]
    Time to maximum plasma concentration (Tmax)

  5. Pharmacokinetic (PK) profile of CA-4948 measured by plasma terminal half-life [ Time Frame: 24- 36 months ]
    Plasma terminal elimination half-life (T 1/2)

  6. To assess efficacy of CA-4948 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 CA-4948 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 CA-4948 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 CA-4948 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 CA-4948 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 CA-4948. At approximately the same timepoint, a peripheral blood sample will be taken to obtain a plasma sample. The respective CA-4948 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 CA-4948 following oral dosing.



Information from the National Library of Medicine

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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, 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

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


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

Locations
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United States, Arizona
Mayo Clinic Recruiting
Phoenix, Arizona, United States, 85054
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 Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Washington
Swedish Cancer Institute Recruiting
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: August 27, 2020
Last Verified: August 2020

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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