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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)

ConditionsRelapsed Hematologic MalignancyRefractory Hematologic MalignancyRelapsed Primary Central Nervous System LymphomaRefractory Primary Central Nervous System Lymphoma
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorCuris, Inc.

About this trial

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

This trial does not accept healthy volunteers

Qualifiers

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.

Disqualifiers

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

Trial design

Design model

Sequential

Treatments tested in this trial

  • Emavusertib

    Drug

    Emavusertib will be provided as a tablet dosage form to be taken BID.

  • Ibrutinib

    Drug

    Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD.

Treatment groups

152 Participants
are divided into 4 treatment groups
Group A: Emavusertib (CA-4948) dose escalationExperimental treatment 1 intervention
Group B: Emavusertib (CA-4948) and ibrutinib dose escalationExperimental treatment 2 interventions
Group C: Emavusertib (CA-4948) and ibrutinib dose expansionExperimental treatment 2 interventions
Group D: Emavusertib (CA-4948) and ibrutinibExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

1

Part A: To determine the safety and tolerability of emavusertib as a monotherapy and in combination with ibrutinib: dose-limiting toxicity (DLT)

The number of participants with a dose-limiting toxicity (DLT) in the first treatment cycle

Time frame
12 months
2

Part A: Maximum tolerated dose (MTD) of emavusertib as a monotherapy and in combination with ibrutinib measured by dose-limiting toxicities (DLTs)

MTD determined by the highest dose level studied at which fewer than 2 out of 6 subjects (\<33%) experience a dose limiting toxicity.

Time frame
12 months
3

Part A: Recommended Phase 2 Dose (RP2D) of emavusertib as a monotherapy and in combination with ibrutinib based on overall tolerability data

RP2D selected based on overall tolerability data from all participants treated at different dose levels and will not exceed the MTD.

Time frame
12 months
4

Part B: Overall Response Rate (ORR) in participants with R/R PCNSL

Time frame
18 months

Secondary outcomes

1

Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC

Area Under the concentration-time curve (AUC)

Time frame
24- 66 months
2

Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax

Maximum plasma concentration (Cmax)

Time frame
24- 66 months
3

Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin

Minimum plasma concentration (Cmin)

Time frame
24- 66 months
4

Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax

Time to maximum plasma concentration (Tmax)

Time frame
24- 66 months

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Curis, Inc.

Lead sponsor

Source ClinicalTrials.gov
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