FDA Grants Orphan Drug Designation to Tolinapant for Treatment of T-Cell Lymphomas

The FDA granted an Orphan Drug designation to tolinapant for the treatment of patients with T-cell lymphomas.

The FDA has granted an Orphan Drug designation to the novel agent tolinapant (ASTX660) for the treatment of patients with T-cell lymphomas, Astex Pharmaceuticals announced in a press release.1

Tolinapant is an oral investigational non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (clAP1/2 and XlAP). Inhibitors of apoptosis proteins (IAPs) are commonly overexpressed in tumor cells and are known to contribute to tumor cell survival, as well as chemotherapy resistance. Tolinapant promotes cell death by inhibiting IAPs.

“T-cell lymphoma remains a challenging disease area with poor prognosis and high unmet medical need,” said Mohammad Azab, MD, president and chief medical officer, Astex Pharmaceuticals, a subsidiary of Otsuka Pharmaceutical, in a statement. “Astex’s development of tolinapant is aimed at bringing a new therapeutic option for patients with this type of cancer. We are delighted that the FDA has granted the orphan drug designation which recognizes the continued need for development of new treatments for patients with rare diseases such as peripheral T-cell lymphoma and cutaneous T-cell lymphoma.”

The agent is currently under evaluation in a phase 1/2 clinical trial (NCT02503423) for the treatment of patients with advanced solid tumors and lymphomas. This is an open-label, dose-escalation study aimed to assess the safety of tolinapant. The primary end points include safety as assessed by number of patients with adverse events, dose-limiting toxicities, abnormal clinical laboratory values, or physical exam results; efficacy assessed by the objective response rate; and efficacy assessed by disease control rate.

The phase 1 portion of the study includes a dose-escalation stage (part 1) that sought to identify the maximum tolerated dose and the recommended phase 2 dose of tolinapant, and part 2, a dose-expansion stage, to confirm the tolerability of the agent at the recommended phase 2 dose. In part 2, patients received this dose on an every-other-week daily dosing regimen, and up to 12 patients were treated in this arm. In part 3 of the phase 1 portion of the study, up to 18 patients received the recommended dose to explore alternative dosing regimens.

According to findings from the phase 1 portion of the study, the maximum tolerated dose was found to be 210 mg/day and the recommended phase 2 dose was set at 180 mg/day.2

A total of 45 patients received doses of tolinapant from 15 mg/day to 270 mg/day. The majority of patients had solid tumors, most commonly colorectal or head and neck cancer, but 2 patients had lymphomas.

Dose-limiting toxicity was observed at 270 mg/day in terms of 3 events of grade 3 increased lipase with or without increased amylase, which was also observed in 1 patient who received the 210-mg/day dosage.

The median progression-free survival was 55 days (95% CI, 54-56) and the median overall survival was 265 days (95% CI, 174-389). Ten patients achieved stable disease and the median duration of stable disease was 150.5 days (95% CI, 49-349). One patient with cutaneous T-cell lymphoma had a clinically meaningful improvement in their skin lesions after 2 cycles of treatment.

The most common treatment-related adverse events observed in the phase 1 portion of the study were fatigue (33%), vomiting (31%), and nausea (27%). Grade 3 or higher treatment-related adverse events were reported in 7 patients, including most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%).

The phase 2 portion of the study, which is ongoing, will stratify patients to 1 of 6 cohorts. Cohort 1 will include patients with recurrent/metastatic head and neck squamous cell carcinoma, cohort 2 will include patients with relapsed/refractory diffuse large B-cell lymphoma, and cohort 3 will include patients with progressive or relapsed peripheral T-cell lymphoma. Cohort 4 includes patients with relapsed/refractory cutaneous T-cell lymphoma, cohort 5 will include other tumor types characterized by a molecular feature that may confer sensitivity to tolinapant, and cohort 6 will include those with cervical carcinoma.

Key secondary end points include pharmacokinetic outcomes in terms of concentration-time curve, maximum concentration, minimum concentration, time to maximum concentration, and samples over time. Other secondary end points also include duration of antitumor response, progression-free survival, overall survival, and assessment of clAP1 engagement.

To be eligible for this study, patients must have a histologically or cytologically confirmed advanced solid tumor or lymphoma that is metastatic or unresectable, and they must have no more standard life-prolonging options. Patients should also have an ECOG performance status of 0 to 2 and acceptable organ function. Patients are ineligible if they have hypersensitivity to tolinapant, poor medical risk, life-threatening illness, HIV or hepatitis B or C infection, brain metastases, or a history of/risk for cardiac disease.


1. Astex Pharmaceuticals announces that tolinapant (ASTX660), a novel antagonist of cellular and x-linked inhibitors of apoptosis proteins, has been granted orphan drug designation for the treatment of t-cell lymphomas by the US FDA. News Release. Astex Pharmaceuticals. August 31, 2020. Accessed September 1, 2020. https://bwnews.pr/31N2vNd

2. Mita MM, LoRusso PM, Papadopoulos KP, et al. A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma. Clin Cancer Res. 2020;26(12):2819-2826. doi:10.1158/1078-0432.CCR-19-1430