First in Human (FIH) Study of GFH009, a Highly Selective Cyclin-Dependent Kinase 9 (CDK9) Inhibitor, in Patients with Relapsed/Refractory (r/r) Hematologic Malignancies (2022)

Background: The key roles of cyclin-dependent kinases in cell proliferation and various aspects of transcription have led to efforts to develop CDK inhibitors as cancer therapeutics. Positive transcription elongation factor b (PTEFb) consisting of Cyclin T and CDK9 is a key regulator of transcription in cancer cells. It is vital for transcription of short-lived gene products, such as MYC and MCL-1, that maintain cancer cell survival. GFH009 is a potent and highly selective CDK9 inhibitor. Here we report preliminary safety and efficacy data from the FIH study of GFH009 in patients with r/r hematologic malignancies (NCT04588922). Methods: This is a phase I, multicenter, dose-escalation trial of GFH009 enrolling patients with relapsed/refractory acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) or lymphoma. The Bayesian optimal interval (BOIN) design is employed in the dose escalation cohorts of 3-6 patients. In the first part of the trial, GFH009 was administered intravenously over 30-60 minutes twice per week. The primary endpoint was to evaluate the safety of GFH009 measured by adverse events using common terminology criteria for adverse event (CTCAE) v5.0 and dose limiting toxicities (DLTs). Disease responses were evaluated using Lugano (2014) for lymphoma, IWG criteria (2003) for AML, and iwCLL (2018) for CLL/SLL. Blood samples were collected and analyzed for pharmacokinetics (PK) and pharmacodynamics (PD). Results: As of 15 July 2022, a total of 46 patients were screened, and 30 received at least one dose of GFH009 as monotherapy, including 16 lymphoma patients in 2.5, 4.5, 9 and 15 mg dose cohorts and 14 AML patients in 9, 15, 22.5 and 30 mg dose cohorts. The median age was 52 (range 18-73), and 53% were male. Nine patients (30%) discontinued treatment due to disease progression, eight (27%) due to subjects’ decision and six (20%) due to lack of efficacy. No DLTs were observed to date. The most common drug related AEs were white blood cell decreased [20.0% (6/30), 6.7% (2/30) of which was ≥ G3], neutrophil count decreased [16.7% (5/30), 6.7% (2/30) ≥ G3] and anemia [13.3% (4/30), 3.3% (1/30) ≥ G3]. G3/G4 treatment emergent AEs recorded in >10% of patients included anemia, white blood cell decreased, platelet count decreased, neutrophil count decreased and pneumonia. The total of 12 serious adverse events (SAEs) occurred in 11 subjects, three of which were drug related. All the drug related SAEs were G3 pneumonia. One death was recorded due to disease progression of AML. Four lymphoma patients (3 in 4.5 mg and 1 in 9 mg) achieved stable disease (SD) including one peripheral T cell lymphoma (PTCL), one diffuse large B-cell lymphoma, one Hodgkin lymphoma and one mucosa-associated lymphoid tissue (MALT) lymphoma. The patient with PTCL at 9 mg dose had 62% decrease in sum of the product of the perpendicular diameters for multiple lesions (SPD) based on computed tomography (CT). The duration of treatment of the PTCL patient and MALT lymphoma patient was 12 weeks and 41 weeks respectively and they continue treatment at the cut-off date. No objective response was observed in AML patients, but two patients, one at 9 mg dose level and one at 15 mg dose level, had decrease of bone marrow blasts ≥ 50%. PK exposure increased in a dose-proportional manner as increasing dose from 2.5 mg to 22.5 mg. The mean half-life ranged from 14.9 h to 17.7 h. Pharmacodynamic assessment of MYC and MCL1 mRNA in whole blood showed post-dose reduction of short half-life mRNA transcripts at higher dose levels. Conclusion: GFH009 as monotherapy is well tolerated at the tested doses and has shown clinical activity in patients with r/r lymphoma. The dose escalation in patients with AML and lymphoma is ongoing. Different dosing regimens are currently being explored for potentially better inhibition on the target. GFH009 add-back in patients refractory to or relapsed while on venetoclax and hypomethylating agents is planned in AML patients. Key words: cyclin-dependent kinases, CDK9 inhibitor, MYC, MCL-1, AML, lymphoma, CLL, SLL, PTCL, MALT lymphoma