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

Overview

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.

Interventions

• Drug Emavusertib
  Emavusertib will be provided as a tablet dosage form to be taken BID.
• Drug Ibrutinib
  Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD.

Primary outcome measures

• Part A: To determine the safety and tolerability of emavusertib as a monotherapy and in combination with ibrutinib: dose-limiting toxicity (DLT) [Time frame: 12 months]
• Part A: Maximum tolerated dose (MTD) of emavusertib as a monotherapy and in combination with ibrutinib measured by dose-limiting toxicities (DLTs) [Time frame: 12 months]
• Part A: Recommended Phase 2 Dose (RP2D) of emavusertib as a monotherapy and in combination with ibrutinib based on overall tolerability data [Time frame: 12 months]
• Part B: Overall Response Rate (ORR) in participants with R/R PCNSL [Time frame: 18 months]
• Part C: ORR in participants with R/R PCNSL [Time frame: 18 months]

Secondary outcome measures (11)

• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC [Time frame: 24- 66 months]
• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax [Time frame: 24- 66 months]
• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin [Time frame: 24- 66 months]
• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax [Time frame: 24- 66 months]
• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life [Time frame: 24- 66 months]
• Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by ORR [Time frame: 24- 36 months]
• 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) [Time frame: 24- 66 months]
• Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by disease control rate (DCR) [Time frame: 24- 36 months]
• 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) [Time frame: 24- 66 months]
• 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) [Time frame: 24 - 66 months]
• 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 [Time frame: up to 66 months]

Eligibility criteria

Inclusion criteria

• Males and females greater than or equal to 18 years of age
• Life expectancy of at least 3 months
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2
• Histopathologically confirmed diagnosis of PCNSL (medical record is acceptable). Cerebral biopsies are not required if imaging reveals typical images of PCNSL.

• 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.
• 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

• 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
• 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).
• 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.
• Active malignancy other than PCNSL requiring systemic therapy
• Previous BTKi treatment (Part C only).
• History of Grade ≥ 3 rhabdomyolysis without complete recovery
• Requirement for urgent therapy due to uncontrolled tumor mass/edema effects.
• Received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1.
• 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

• 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)
• Prior history of hypersensitivity or anaphylaxis to emavusertib, ibrutinib or any of their excipients.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 27 centers

• St. Joseph's Hospital and Medical Center — Phoenix
• Mayo Clinic — Phoenix
• City of Hope — Duarte
• Providence St. John's Health Center — Santa Monica
• UCLA Department of Medicine - Hematology/Oncology — Santa Monica
• Smilow Cancer Hospital at Yale-New Haven — New Haven
• Mayo Clinic — Jacksonville
• Northwestern Memorial Hospital — Chicago
• … and 19 more centers

France · 4 centers

• Institut Bergonie — Bordeaux
• Hopital de la Timone — Marseille
• Hospital Pitie Salpetriere — Paris
• Institut Curie Hospital — Paris

Italy · 4 centers

• Università di Torino Croce e Carle — Cuneo
• SODc Ematologia Azienda Ospedaliera Universitaria Careggi — Florence
• IRST - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori — Meldola
• IRCCS San Raffaele Scientific Institute — Milan

Israel · 3 centers

• Hematology Department Soroka UMC / Heanatology Department — Beersheba
• Rambam Medical Center — Haifa
• Hadassah Medical Center / Ein-Carem — Jerusalem

Poland · 3 centers

• Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz — Gdansk
• Oddzial Kliniczny Hematologii — Krakow
• NarodowyInstytutu Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytutu Badawczy — Warsaw

Spain · 3 centers

• University Hospital Vall d'Hebron — Barcelona
• MD Anderson Cancer Center Madrid — Madrid
• Hospital Universitario Virgen del Rocio — Seville

Czechia · 1 center

• Všeobecná fakultní nemocnice v Praze — Prague

Identifiers

NCT: NCT03328078 · CA-4948-101 · 2024-513312-95-00 · 2022-000891-20

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗