Clinical trial NCT03328078: CA-4948-101: Open-Label, Dose Escalation and Expansion Trial of Emavusertib (CA-4948) in Relapsed or Refractory Primary Central Nervous System Lymphoma (R/R PCNSL)
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 Primary Central Nervous System Lymphoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Relapsed Hematologic Malignancy
Refractory Hematologic Malignancy
Relapsed Primary Central Nervous System Lymphoma
Refractory Primary Central Nervous System Lymphoma
Keywords: MYD88
IRAK4
NHL
PCNSL
Lymphoma
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Relapsed/refractory Central Nervous System (CNS) Lymphoma
Systemic Lymphoma with Concurrent CNS Lymphoma
Systemic Lymphoma with a History of Treated CNS Lymphoma
Ibrutinib
Bruton tyrosine kinase inhibitor (BTKi)
Primary CNS Lymphoma
Lead sponsor: Curis, Inc.
Sponsor class: INDUSTRY
First posted: 2017-11-01
Enrollment: 152
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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). Enrollment is closed for Part A1 and A2. Part B will comprise two expansion cohorts to assess efficacy and safety of emavusertib in combination with ibrutinib in R/R PCNSL. Part C will comprise three cohorts to assess the efficacy and safety of emavusertib monotherapy, ibrutinib monotherapy, and emavusertib in combination with ibrutinib in participants with R/R PCNSL who are naïve to BTKi treatment.
Primary purpose: TREATMENT

Brief summary: This is a multi-center, open-label study to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib alone or in combination with ibrutinib in adult participants with relapsed or refractory (R/R) hematologic malignancies.

This trial will be completed in four parts. In Part A1, emavusertib will be evaluated first in a dose escalating monotherapy setting to establish the safety and tolerability (complete). In Part A2, emavusertib will be evaluated in combination with ibrutinib at 560 milligrams (mg) once daily (QD) or 420 mg QD as indicated by disease (Part A2 complete).

Part B will comprise 2 cohorts to assess safety and efficacy of emavusertib in combination with ibrutinib in participants with R/R primary central nervous system lymphoma (PCNSL) who have directly progressed on a bruton tyrosine kinase inhibitor (BTKi). In this part of the study, emavusertib will be dosed at 100 mg or 200 mg twice daily (BID) in combination with ibrutinib in 28-day treatment cycles.

Part C will comprise 3 treatment arms in the second-line setting to assess the efficacy and safety of emavusertib monotherapy, ibrutinib monotherapy, and emavusertib in combination with ibrutinib in participants with R/R PCNSL who are naïve to BTKi treatment. In this part of the study, eligible second-line participants with R/R PCNSL who are naïve to BTKi treatment will be randomized 1:1:1 to 1 of 3 treatment arms: (1) emavusertib 200 mg BID, (2) ibrutinib 560 mg QD, or (3) emavusertib 200 mg BID in combination with ibrutinib 560 mg QD.


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 0, 1 or 2
4. Histopathologically confirmed diagnosis of PCNSL (medical record is acceptable). Cerebral biopsies are not required if imaging reveals typical images of PCNSL.

   1. Participants with parenchymal lesions must have unequivocal evidence of disease progression (e.g., presence of at least 1 measurable target lesion \[≥ 10 millimeters (mm) and ≤ 40 mm in the longest diameter on brain magnetic resonance imaging \[MRI\] or head computed tomography \[CT\] on imaging within 28 days prior to Cycle 1 Day 1\]). In cases where the tumor size is smaller but still measurable and located at a critical central nervous system (CNS) location, disabling the participant and/or causing symptoms, this participant may be eligible following a discussion with the Sponsor Medical Monitor.
   2. For participants limited to leptomeningeal involvement, cerebrospinal fluid (CSF) analysis (cytology and/or flow cytometry) with or without additional imaging (MRI) of the spine as clinically indicated is required to document abnormal cells within 28 days prior to Cycle 1 Day 1.

Exclusion Criteria for Part B and Part C

1. Participants with only intraocular PCNSL without brain lesion or CSF involvement, T-cell lymphoma, systemic presence of lymphoma, or non-CNS lymphoma metastatic to the CNS
2. Evidence of systemic lymphoma. This must be demonstrated by a positron emission tomography (PET) scan (or CT scan with contrast if applicable) of the chest, abdomen, and pelvis at Screening (testicular ultrasound may be considered to exclude a testicular lymphoma disseminated to the brain).
3. Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) or prior history of systemic lymphoma, unless the participant has been free of the disease for ≥ 3 years.
4. Active malignancy other than PCNSL requiring systemic therapy
5. Previous BTKi treatment (Part C only).
6. History of Grade ≥ 3 rhabdomyolysis without complete recovery
7. Requirement for urgent therapy due to uncontrolled tumor mass/edema effects.
8. Received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1.
9. Received prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1; allogeneic hematopoietic stem cell transplant (HSCT) within 60 days prior to Cycle 1 Day 1; or had clinically significant graft-versus-host disease (GVHD) requiring ongoing up-titration of immunosuppressive medications prior to Screening (with the exception of a BTKi for Part B only).

   Note: The use of a stable or tapering dose of immunosuppressive therapy post-HSCT and/or topical steroids for ongoing skin GVHD is permitted with Sponsor Medical Monitor approval
10. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1 (with the exception of ibrutinib or other BTKi for Part B only, which may be continued until the day before Cycle 1 Day 1)
11. Prior history of hypersensitivity or anaphylaxis to emavusertib, ibrutinib or any of their excipients.

Primary outcomes:
measure: Part A: To determine the safety and tolerability of emavusertib as a monotherapy and in combination with ibrutinib: dose-limiting toxicity (DLT)
timeFrame: 12 months
measure: Part A: Maximum tolerated dose (MTD) of emavusertib as a monotherapy and in combination with ibrutinib measured by dose-limiting toxicities (DLTs)
timeFrame: 12 months
measure: Part A: Recommended Phase 2 Dose (RP2D) of emavusertib as a monotherapy and in combination with ibrutinib based on overall tolerability data
timeFrame: 12 months
measure: Part B: Overall Response Rate (ORR) in participants with R/R PCNSL
timeFrame: 18 months
measure: Part C: ORR in participants with R/R PCNSL
timeFrame: 18 months
Secondary outcomes:
measure: Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC
timeFrame: 24- 66 months
measure: Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax
timeFrame: 24- 66 months
measure: Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin
timeFrame: 24- 66 months
measure: Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax
timeFrame: 24- 66 months
measure: Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life
timeFrame: 24- 66 months
measure: Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by ORR
timeFrame: 24- 36 months
measure: Parts A, B and C: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib and ibrutinib as monotherapy measured by duration of response (DOR)
timeFrame: 24- 66 months
measure: Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by disease control rate (DCR)
timeFrame: 24- 36 months
measure: Parts A, B and C: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib and ibrutinib as monotherapy measured by progression free survival (PFS)
timeFrame: 24- 66 months
measure: Parts A, B and C: To assess efficacy of emavusertib as a monotherapy, in combination with ibrutinib and ibrutinib as monotherapy measured by overall survival (OS)
timeFrame: 24 - 66 months
measure: Parts B and C: To assess the safety and tolerability of emavusertib as monotherapy, ibrutinib as monotherapy and emavusertib in combination with ibrutinib in participants with R/R PCNSL
timeFrame: up to 66 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Santa Monica
country: United States
facility: Providence St. John's Health Center
state: California
city: Santa Monica
country: United States
facility: UCLA Department of Medicine - Hematology/Oncology
state: California
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale-New Haven
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: Fred and Pamela Buffett Cancer Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Mt Sinai
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center, Duke Cancer Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Providence Neurological Specialties West
state: Oregon
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hilman Cancer Center
state: Pennsylvania
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, University of Utah
state: Utah
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Prague
country: Czechia
facility: Všeobecná fakultní nemocnice v Praze
city: Bordeaux
country: France
facility: Institut Bergonie
city: Marseille
country: France
facility: Hopital de la Timone
city: Paris
country: France
facility: Hospital Pitie Salpetriere
city: Paris
country: France
facility: Institut Curie Hospital
city: Be'er Sheva
country: Israel
facility: Hematology Department Soroka UMC / Heanatology Department
city: Jerusalem
country: Israel
facility: Hadassah Medical Center / Ein-Carem
city: Cuneo
country: Italy
facility: Università di Torino Croce e Carle
city: Firenze
country: Italy
facility: SODc Ematologia Azienda Ospedaliera Universitaria Careggi
city: Meldola
country: Italy
facility: IRST - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: IRCCS San Raffaele Scientific Institute
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz
city: Kraków
country: Poland
facility: Oddzial Kliniczny Hematologii
city: Warsaw
country: Poland
facility: NarodowyInstytutu Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytutu Badawczy
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
Study officials:
References: