CDK9 Inhibitor GFH009 Advances in Phase 1 Trial in Relapsed/Refractory Lymphoma and AML

Dragan Cicic, MD

The novel and highly selective CDK9 inhibitor GFH009 demonstrated encouraging tolerability in patients with advanced, relapsed/refractory acute myeloid leukemia (AML) and lymphoma, according to updated findings from an ongoing, phase 1 dose-escalation trial (NCT04588922).¹

In the AML population, no dose-limiting toxicities were reported in patients who received the fifth dose level of 22.5 mg of twice weekly GFH009, including no cases of grade 3 or 4 neutropenia. As such, the cohort is proceeding to the sixth and last planned dose level of 30 mg twice weekly.

In the lymphoma population, the 15-mg dose level cohort has completed enrollment. Safety assessments for this cohort are currently underway. In the prior 9-mg dose level cohort, one patient with peripheral T-cell lymphoma who was refractory to 3 prior lines of therapy demonstrated a partial response.

“We continue to see positive results in our clinical efforts for GFH009, especially in assessing the safety in patients with lymphoma and AML,” Dragan Cicic, MD, senior vice president of Clinical Development at SELLAS, stated in a press release. “The clinical process for safety is to determine the highest dose level patients can tolerate without experiencing adverse [effects (AEs)]. Not only does GFH009 appear to be safe at the dose levels studied to date, but we have also observed efficacy in lower dose levels. These results are encouraging as we continue to increase dose levels and assess accordingly.”

The open-label study, which consists of a dose-escalation and dose-expansion portion, is enrolling patients with relapsed/refractory hematologic malignancies including AML, chronic lymphocytic leukemia, small lymphocytic lymphoma, and lymphoma.² 

In April 2022, the manufacturer, Sellas Life Sciences Group, announced that the first patient with AML had been enrolled into the fifth dose level out of the 6 planned dose cohorts, at which point no dose-limiting toxicities (DLTs) had been reported in the first four dose levels: 2.5 mg, 4.5 mg, 9 mg, and 15 mg twice weekly.³

Moreover, significant anti-leukemic effects had been reported at the 9-mg and 15-mg dose levels in patients with resistance to standard-of-care treatments, with 2 patients refractory to, or relapsed after, venetoclax (Venclexta) experiencing at least a 50% reduction in bone marrow blasts following GFH009 monotherapy.

Notably, the 2 patients each previously had received 6 lines of therapy with venetoclax, chemotherapy, and experimental agent combinations.

To be eligible for enrollment, patients have to be at least 18 years of age and have cytological or histologically confirmed relapsed/refractory hematologic malignancies; total bilirubin of no greater than 1.5 x the upper limit of normal (ULN), except for patients with Gilbert’s syndrome, who are eligible if their total bilirubin is less than 3 x ULN or if their direct bilirubin is less than 1.5 x ULN; and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) no greater than 2.5 x ULN.

For patients with hepatic metastases, AST and ALT have to be no greater than 5 x ULN. Additionally, amylase and lipase can be no greater than 1.5 x ULN; and electrolytes and uric acid levels have to be within normal limits or correctable with medical intervention.

Women of childbearing potential and men with a partner of childbearing potential must consent to use 2 highly effective methods of contraception during GFH009 treatment and for an additional 90 days after the last administration of study drug.

In the dose-escalation portion, patients will receive escalated dose levels following the Bayesian optimal interval design. In the expansion phase, doses will be determined based on tumor type.

The primary outcome measures are the safety and tolerability of GFH009 quantified by the incidence of DLTs and the incidence and severity of all AEs. Secondary outcome measures include pharmacokinetic parameters measured by the area under the plasma concentration-time curve from zero to the time of the last measurable concentration and infinity.

Following the completion of the phase 1 trial, the company plans to launch a phase 2 trial with GFH009 in combination with venetoclax and azacitidine in patients with AML.

References

1. SELLAS Life Sciences provides clinical update for GFH009 ongoing phase 1 clinical trial. News release. Sellas Life Sciences Group. June 27, 2022. Accessed June 28, 2022. https://yhoo.it/3u9cx9r
2. A study of GFH009 in patients with hematologic malignancies. ClinicalTrials.gov. Updated May 14, 2021. Accessed June 28, 2022. https://clinicaltrials.gov/ct2/show/NCT04588922
3. SELLAS Life Sciences’ Newly Licensed GFH009 Asset Shows Significant Anti-Leukemic Effect in Acute Myeloid Leukemia Patients Relapsed/Refractory to Venetoclax in Ongoing Phase 1 Study. News release. Sellas Life Sciences Group. April 11, 2022. Accessed June 28, 2022. https://bit.ly/39WJM95