TP-3654 Demonstrates Favorable Tolerability, Early Clinical Activity in R/R Myelofibrosis

Lindsay AM Rein, MD

The oral selective PIM1 kinase inhibitor TP-3654 appeared to be well tolerated and to show early signals of spleen volume reduction, symptom improvement, and correlating cytokine reductions in patients with relapsed or refractory myelofibrosis, according to preliminary data from the phase 1/2 TP-3654-102 study (NCT04176198) presented during the 2023 ASH Annual Meeting.¹

In the doses/regimens assessed, the agent appeared to be safe, with no dose-limiting toxicities (DLTs) observed. Moreover, the maximum tolerated dose (MTD) had not yet been reached. The most common adverse effects (AEs) included grade 1 or 2 diarrhea, nausea, and vomiting, and toxicities were found to be transient and manageable with supportive care.

Clinical activity was reported in those with a baseline platelet count of less than 100 x 10⁹/L or hemoglobin count of less than 10 g/dL. In evaluable patients (n = 20), 20% of patients achieved a spleen volume reduction (SVR) of at least 35%, 30% of patients had a SVR of 25%, and 55% had a SVR of 10%. Fifty-five percent of patients experienced a 50% or greater improvement in TSS.

“Patients tolerate therapy well and are on therapy for longer than a year,” Lindsay AM Rein, MD, a hematologic oncologist at Duke University Medical Center in Durham, North Carolina, said in a presentation. “Preliminary signs of early clinical activity [were observed….] Symptom reductions are observed early and [are] sustained.”

Although the utilization of JAK inhibitors has improved outcomes for patients with myelofibrosis, and has since become the standard of care, these agents are limited by thrombocytopenia and/or anemia and the lack of disease-modifying effects. Although emerging combination regimens seek to raise the bar, they are associated with overlapping toxicities, such as cytopenia. As such, a need remains for agents that have limited myelosuppressive effects.

Patients with myelofibrosis are known to have elevated PIM1 expression, and PIM1 is a proto-oncogene that is partially regulated through the JAK/STAT, NF-Kappa B, and ERG pathways. “PIM1 kinase upregulation leads to cytokine increases relevant to immune activation and fibrosis,” Rein noted.

Preclinical data have demonstrated that PIM1 knockout prevented the progression of myelofibrosis; PIM2 knockout did not have any effect on the disease. Additionally, PIM1 knockout did not result in platelet count reduction but Pan-PIM knockout did in mice. “Investigational therapies which selectively inhibit PIM1 may provide clinical benefit and potential disease-modifying benefits for myelofibrosis patients while avoiding myelosuppressive AEs,” Rein said.

In JAK2^V617F and MPL^W515L myelofibrosis mouse models, TP-3654 monotherapy or paired with ruxolitinib (Jakafi) resulted in decreased spleen size and reduced bone marrow fibrosis.

The global phase 1/2 study enrolled patients with primary, post–polycythemia vera (post-PV), or post–essential thrombocytopenia (post-ET) myelofibrosis. Patients must have been relapsed, refractory, intolerant to or not candidates for JAK inhibitors.

To participate, they were required to have intermediate-1, intermediate-2, or high-risk disease per the Dynamic International Prognostic Scoring System (DIPSS); a platelet count of at least 25 x 10⁹/L; an ECOG performance status of 0 to 2; splenomegaly; and at least 2 symptoms per version 4 of The Myelofibrosis Symptom Assessment Form.

“I want to point out a key eligibility criterion that I think is of particular interest and importance, which is the platelet threshold,” Rein said. “You’ll see that the platelet count required for enrollment onto the study was 25,000/L, which is interesting and novel in the context of our current clinical trial designs in the landscape in that it is lower in comparison to the others.”

In the first phase of the study, TP-3654 is under evaluation as a single agent given at escalating doses ranging from 480 mg once daily (n = 1), to 720 mg once daily (n = 2), to 360 mg twice daily (n = 5), to 480 mg twice daily (n = 13), to 720 mg twice daily (n = 10), to 1440 mg twice daily. “We are currently enrolling into the phase 1 portion of this,” Rein said. Once the MTD or the recommended phase 2 dose was established, the phase 2 dose-expansion phase of the research will be initiated.

The primary end point of the study is safety and tolerability, and key secondary end points include SVR, total symptom score (TSS) reduction, overall survival, change in bone marrow fibrosis, and pharmacokinetics.

In the 31 patients enrolled, the median age was 73 years (range, 56-84) and about half (52%) were male. The median spleen length and volume was 10 cm (range, 0-30) and 1816 cm3 (range, 609-6006), respectively. The median TSS was 20 (range, 4-62). The median platelet count was 103 x 109/L (range, 26-520) and 52% of patients had a count of at least 100 x 109/L. The median hemoglobin count was 9.1 g/dL (range, 5.9-13.7) and 61% had a count that was under 10 g/dL. Twenty-nine percent of patients required transfusions.

In terms of disease subtype, 45% had primary myelofibrosis, 39% had post-PV myelofibrosis, and 16% had post-ET myelofibrosis. With regard to DIPSS risk group, most patients had intermediate-2 risk disease (45%), followed by intermediate-1 risk disease (32%), and high-risk disease (23%). Seventy-seven percent of patients had a JAK2 V617F driver mutation. The majority of patients (81%) received 1 prior JAK inhibitor; 16% had received 2 or more of these agents. In terms of response to JAK inhibition, 48% had relapsed, 26% were intolerant, and 23% were resistant.

The mean hemoglobin and platelet count continued to be stable throughout the treatment period of 24 weeks.

Responses achieved with TP-3654 were durable with patients on treatment for longer than 1 year. Of the 31 patients, 18 were still on active treatment as of the data cutoff date of October 20, 2023. The remaining 13 patients discontinued because of physician decision (n = 2), patient withdrawal (n = 2), disease progression (n = 3), and others (n = 6).

“TP-3654 showed early responses. Patients were responding as early as 4 weeks after initiation of therapy,” Rein underscored. “The other point [to make] is the durability of this response.”

Treatment-emergent changes in inflammatory cytokines were observed, she added. “Patients who had higher reductions in cytokines had an associated higher reduction in their TSS,” Rein said. To examine the data in a different way, investigators performed a principal component analysis. Preliminary analysis at week 12 demonstrated correlation of cytokine reductions and symptom involvement with TP-3654.

Regarding safety, the most common treatment-emergent adverse effects experienced by at least 10% of patients included diarrhea (grade 1, 54.8%; grade 2, 16.1%; grade ≥3, 6.5%), nausea (38.7%; 9.7%; 0%), vomiting (22.6%; 16.1%; 0%), abdominal pain (12.9%; 12.9%; 3.2%), fatigue (12.9%; 12.9%; 0%), increased blood bilirubin (6.5%; 12.9%; 6.5%), reduced appetite (6.5%; 6.5%; 3.2%), abdominal distension (6.5%; 6.5%; 0%), hyperhidrosis (6.5%; 6.5%; 0%), dyspnea (6.5%; 6.5%; 0%), reduced platelet count (0%; 6.5%; 16.1%), and anemia (0%, 3.2%; 9.7%).

Infections were grade 1 or 2 except 1 event of unrelated grade 3 urinary tract infection.

“Enrollment is ongoing as TP-3654 monotherapy,” Rein concluded. “Emerging clinical data support development of TP-3654 in combination with JAK inhibitors.”

Reference

1. Rein LAM, El Chaer F, Yuda J, et al. Phase 1/2 study of TP-3654, a selective PIM1 kinase inhibitor: preliminary data showed clinical activity and cytokine reductions in relapsed/refractory myelofibrosis patients. Blood. 2023;142(suppl 1):626. doi:10.1182/blood-2023-180164