A Study of JNJ-88549968 for the Treatment of Calreticulin (CALR)-Mutated Myeloproliferative Neoplasms

Study Overview
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Brief Summary
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The purpose of this study is to characterize safety and to determine the Recommended Phase 2 Dose (RP2D[s]) and optimal dosing schedule(s) of JNJ-88549968, in part 1 (Dose Escalation); to characterize the safety of JNJ- 88549968 at RP2D(s), in part 2 (Cohort Expansion).

Official Title
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A First-in-Human Study of the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-88549968, a T-cell Redirecting Bispecific Antibody for CALR-mutated Myeloproliferative Neoplasms

Conditions
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Myeloproliferative Disorders, Essential Thrombocythemia, Neoplasms, Myelofibrosis

Intervention / Treatment
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* Drug: JNJ-88549968


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be greater than or equal to (>=) 18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever the greater) at the time of informed consent Positive for a calreticulin (CALR) driver mutation of essential thrombocythemia (ET) or myelofibrosis (MF) Participants with ET and MF with risk characteristics as described in the protocol Have an Eastern Cooperative Oncology Group (ECOG) performance status grade of less than or equal to (<=) 2 Exclusion Criteria: Known allergies, hypersensitivity, or intolerance to the excipients of the study treatment Concurrent or recently diagnosed or treated malignancies present at the time of participant screening. Exceptions are squamous and basal cell carcinoma of the skin, carcinoma in situ of the cervix, and any malignancy that is considered cured or has minimal risk of recurrence within 1 year of first dose of study treatment in the opinion of both the investigator and sponsor's medical monitor. Participants cured of another malignant disease with no sign of relapse greater than or equal to (>=) 3 years after treatment ended are allowed to enter the study Prior solid organ transplantation Either of the following regarding hematopoietic stem cell transplantation: Prior treatment with allogenic stem cell transplant less than or equal to (<=) 6 months before the first dose of JNJ-88549968 or Evidence of graft versus host disease (GVHD) that requires immunosuppressant therapy History of clinically significant cardiovascular disease within 6 months prior to the first dose of study treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Part 1) and Dose Expansion (Part 2)<br>In dose escalation (Part 1), participants will receive JNJ-88549968. The dose will be escalated sequentially to determine the recommended phase 2 dose (RP2D) and optimal dosing schedule(s) based on safety, pharmacokinetic, pharmacodynamic, and preliminary assessment of efficacy across several dose regimens. In dose expansion (Part 2), participants will receive JNJ-88549968 at the RP2D regimen(s) determined in dose escalation (Part 1). | Drug: JNJ-88549968<br>* JNJ-88549968 will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Dose Limiting Toxicity (DLT) | Number of participants with DLT will be reported. The DLTs are specific adverse events and are defined as any of the following: high grade non-hematologic toxicity, or hematologic toxicity. | Approximately up to 35 days after first dose of study treatment | 
| Part 1 and 2: Number of Participants with Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Up to 2 years | 
| Part 1 and 2: Number of Participants with Adverse Events (AEs) by Severity | An adverse event is any untoward medical occurrence in a clinical study participant that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from grade 1 (mild) to grade 5 (death). Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening and Grade 5= death related to adverse event. Cytokine release syndrome (CRS) and associated neurologic toxicity events (immune effector cell-associated neurotoxicity syndrome events [ICANS]) will be graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Serum Concentration of JNJ-88549968 | Serum samples will be analyzed to determine concentrations of JNJ-88549968. | Up to 2 years | 
| Part 1 and 2: Number of Participants With Presence of Anti-Drug Antibodies to JNJ-88549968 | Number of participants with presence of anti-drug antibodies to JNJ-88549968 will be reported. | Up to 2 years | 
| Part 1 and 2: Overall Response Rate | ORR is defined as the percentage of participants who achieve partial response (PR) and complete response (CR) according to modified International Working Group-Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) criteria and modified European Leukemia Net (ELN) consensus report. | Up to 2 years | 
| Part 1 and 2: Complete Response (CR) Rate | CR rate is defined as the percentage of participants who achieve a best response of CR according to disease as defined in modified IWG-MRT criteria and modified ELN consensus report. | Up to 2 years | 
| Part 1 and 2: Time to Response (TTR) | TTR is defined for participants who achieved PR or CR as the time from the first dose of study treatment to first response of PR or CR according to modified IWG-MRT criteria and modified ELN consensus report. | Up to 2 years | 
| Part 1 and 2: Duration of Response (DOR) | DOR is defined for participants who achieved PR or CR as the time between the date of initial documentation of PR or CR to the date of first documented evidence of disease progression, as defined in modified IWG-MRT criteria and modified ELN consensus report, or death, whichever comes first. | Up to 2 years | 
| Part 2: Change From Baseline in Myeloproliferative Neoplasm (MPN) Symptom Burden | Change from baseline in MPN symptom burden assessed using patient reported outcome (PRO) questionnaire will be reported in this outcome measure. | Baseline up to 2 years |