Novel BTK Inhibitor Well Tolerated in Patients with CLL, Other B-Cell Malignancies

Patients with B-cell malignancies responded well to treatment with the covalent BTK inhibitor TG-1701 at all dose levels in patients.

Updated results from this phase 1/2 trial were presented virtually during the 2021 ASCO Annual Meeting.

While patients with chronic lymphocytic leukemia and other B-cell malignancies have benefitted from treatment with BTK inhibitor monotherapies, complete responses and deep remissions remain rare. TG-1701 is a covalently bound BTK inhibitor that has demonstrated superior selectivity vs other agents, such as Imbruvica (ibrutinib).

In the dose-escalation trial, which included disease-specific groups of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenström macroglobulinemia, the primary objective was to examine the safety and efficacy of TG-1701 alone and in combination with ublituximab/Ukoniq (umbralisib). Additionally, investigators sought to establish the recommended phase 2 dose for the monotherapy and combination regimen.

The trial enrolled patients who were relapsed or refractory to prior standard treatment and had histologically confirmed chronic lymphocytic leukemia or B-cell lymphoma warranting systemic treatment.

The dose-escalation portion of the trial included a TG-1701 monotherapy group and a TG-1701 plus ublituximab/Ukoniq combination group. After the optimal dose had been determined, the trial then moved on to focus on the disease-specific groups, which examined both the single-agent and combination regimens.

Oral TG-1701 was continuously administered daily in 28-day cycles. In the combination groups, an escalating dose of TG-1701 was administered daily, plus an oral dose of Ukoniq at 800 milligrams or 600 milligrams daily and an intravenous dose of ublituximab at 900 milligrams on specific days and cycles.

In the dose-escalation monotherapy group, patients received TG-1701 at 100 milligrams daily, 200 milligrams daily, 300 milligrams daily and 400 milligrams daily.

In the dose-escalation combination group, patients received TG-1701 at 100 milligrams daily and 200 milligrams daily plus ublituximab/Ukoniq. Additionally, patients in the group who received TG-1701 at 300 milligrams daily also received Ukoniq at the 600 milligrams daily dose plus ublituximab at the designated trial dose.

Among the patients who enrolled on the study, the median age was 68 and 69 in the single-agent and combination groups, respectively. Approximately half the total population was men and patients received a median of one prior line of therapy in the single-agent group and two in the combination group.

Of the 125 total patients enrolled on the study, 97 are still receiving ongoing treatment across all groups.

The maximum-tolerated dose of the BTK inhibitor was not achieved in patients who received TG-1701 monotherapy up to a dose of 400 milligrams daily. The efficacy dose-escalation group, which administered 100 milligrams to 400 milligrams of single-agent TG-1701 daily, reported an overall response rate (patients with a partial or complete response to treatment) of 57% after a median follow up of 20.3 months, while the disease-specific monotherapy group, which administered a 200-milligram dose of the agent, yielded an overall response rate of 95% after a median follow up of 12.2 months in patients with chronic lymphocytic leukemia, 65% in patients with mantle cell lymphoma and 95% in patients with Waldenström macroglobulinemia.

In the chronic lymphocytic leukemia group, a single-agent 300-milligram dose yielded an overall response rate of 100% at a median follow up of 8.6 months. Additionally, a dose-escalation group that combined 100 milligrams to 300 milligrams of TG-1701 with ublituximab and Ukoniq daily achieved an overall response rate of 79% at a median follow up of 15.6 months across multiple B-cell malignancies, with a complete response rate of 21%.

“The combination TG-1701 with ublituximab/(Ukoniq) has been well-tolerated and dose escalation continues,” lead study author Dr. Chan Cheah, a clinical professor at the University of Western Australia Medical School, said during an oral presentation on the data. “The combination regimen is associated with encouraging clinical activity, including early complete responses. This study continues enrollment and future registration trials are being planned.”

Across most study groups, the most common reason for treatment discontinuation was disease progression. Notably, two patients discontinued due to non-treatment related side effects in the 200-milligram disease-specific group.

In terms of safety, the most common side effects were mild to moderate in severity and few severe or worse events were reported. In the dose-escalation monotherapy group, the most common any-grade side effects were respiratory tract infection (36%), constipation (32%) and bruising (28%), with common any-grade hematologic and lab abnormalities including neutropenia (low levels of a type of white blood cell called neutrophils; 24%), alanine aminotransferase increase (indication of liver damage; 24%) and aspartate aminotransferase (AST) increase (20%). The most common any-grade side effects in both the disease-specific and chronic lymphocytic leukemia monotherapy groups were respiratory tract infection (10% for each). Common any-grade hematologic and lab abnormalities included neutropenia (13%), anemia (11%) and AKT increase (8%) in the disease-specific group. In the chronic lymphocytic leukemia group, this included alanine aminotransferase increase (15%), aspartate aminotransferase increase (indication of injury mainly to the liver or muscles; 15%) and neutropenia (10%).

Severe or worse side effects included respiratory tract infection (8%) and rash (4%) in the dose-escalation group and COVID-19 (2% and 10%) in the disease-specific and chronic lymphocytic leukemia groups, respectively. In terms of hematologic and lab abnormalities, the most common severe or worse side effects included alanine aminotransferase increase (12%) in the dose escalation group and neutropenia (8% and 10%) in the disease-specific groups and chronic lymphocytic leukemia groups, respectively.

In the combination therapy group, the most common any-grade side effects were diarrhea (47%), chest tightness/facial flushing (47%), bruising (47%), nausea (32%) and high blood pressure (32%). Severe side effects included diarrhea (11%), chest tightness and flushing (5%), high blood pressure (5%) and nausea (5%). Moreover, 11% and 5% of patients experienced life-threatening neutropenia and alanine aminotransferase increase, respectively.

“In terms of laboratory abnormalities, neutropenia was the most common (severe) or higher (side effect), seen in 8% of patients all together,” Cheah said.

Investigators concluded that these findings provide the rationale for further daily dosing with TG-1701.

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