A Phase 1b Study of CLN-049 in Combination With Azacitidine and Venetoclax in AML Patients

Official title

A Phase 1b Dose Escalation and Dose Expansion Study of CLN 049 in Combination With Azacitidine and Venetoclax for the Treatment of Adult Patients With Newly Diagnosed, Acute Myeloid Leukemia

Overview

A Phase 1b, open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenously (IV) administered CLN-049 in combination with azacitidine (Aza) and venetoclax (Ven) in patients with newly diagnosed (ND) AML.

Interventions

• Drug CLN-049
  CLN-049 will be initiated using two step-up doses (SUDs), followed by the first target dose (TD) one week later, and weekly thereafter.
• Drug Azacitidine
  Azacitidine 75 mg/m2 will initially be administered sub-cutaneous or intravenous on days 1 through 7 of a 28-day cycle
• Drug Venetoclax
  Venetoclax will initially be administered orally on days 1 through 28 of a 28-day cycle and then reduced to days 1 through 14 in consolidation cycles.

Primary outcome measures

• Incidence and severity of adverse events (AEs)/adverse events of special interest (AESIs)/serious adverse events (SAEs) [safety and tolerability] of CLN-049 combined with azacitidine and venetoclax [Time frame: 48 weeks]
• Determine recommended dose/schedule of CLN-049 in combination with azacitidine and venetoclax [Time frame: 48 weeks]

Eligibility criteria

Inclusion criteria

• Patients aged ≥ 18 years of age with newly diagnosed, previously untreated AML (including MDS/AML)
• Patients are not candidates for intensive induction chemotherapy because they are either unfit or otherwise clinically unsuitable for anthracycline/ cytarabine-based induction therapy
• White blood cell (WBC) count at the time of C1D1 ≤ 20,000/μL
• Patients must have previously untreated AML; hydroxyurea for cytoreduction is permitted up to C1D1. Prior therapy for MDS is allowed except for hypomethylating agents and venetoclax.
• Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 2
• The patient's laboratory values meet the following criteria:

• Creatinine clearance (CrCl) ≥ 45 mL/min;
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN

Exclusion criteria

• Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML to enter the study).
• Diagnosis of acute promyelocytic leukemia or PML:RARA-positive AML.
• Chronic myeloid leukemia in blast phase or AML with BCR:ABL1.
• Mixed phenotype acute leukemia or acute leukemia of ambiguous lineage.
• Active CNS involvement by AML.
• Signs of leukostasis requiring urgent therapy.
• Prior organ allograft, or prior allogeneic hematopoietic stem cell transplant within the last 12 months, or with active graph-versus-host disease.
• Treatment with systemic glucocorticoid therapy or other immune-suppressive drugs ≤ 14 days prior to the first dose of CLN-049.
• Patients with concomitant second malignancies requiring active treatment in the past 12 months, or if additional therapy is required or anticipated during study participation.
• Patients with any active autoimmune disease or a history of known or suspected autoimmune disease, or history of a syndrome that requires systemic corticosteroids or immunosuppressive medications
• Active uncontrolled infection until infection is treated and brought under control.
• Has a history of, or a positive test for human immunodeficiency virus (HIV) 1/2 or primary immunodeficiency disease such as HIV.
• Known history of hepatitis B, hepatitis C (HCV) infection, or acute hepatitis A.
• Active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
• Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to Grade 1 or less
• History of the following events in conjunction with prior treatment with immunotherapy: Grade 3 or greater neurotoxicity, ocular toxicity, pneumonitis, myocarditis, or colitis; liver dysfunction meeting the laboratory criteria for Hy's Law.
• Live virus vaccines within 28 days of the first dose of CLN-049, during treatment, and until the end of last dose of CLN-049.
• QT interval corrected for heart rate using Fridericia's formula (QTcF) of ≥ 480 milliseconds.
• Patient has a history of drug-related anaphylactic reactions to any components of CLN-049, or a history of Grade 4 anaphylactic reaction to any bispecific molecule or monoclonal antibody therapy.
• Known history of prior human anti-human antibody response.

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 · 3 centers

• City of Hope — Duarte
• New York University Langone Health — New York
• MD Anderson — Houston

Identifiers

NCT: NCT07722767 · CLN-049-AML-103

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗