Aprea Therapeutics is accelerating enrollment in its ongoing Phase I trial of its targeted cancer therapy APR-1051, one of the precision oncology drug developer’s two lead programs, and expanding its indications under study after seeing early signs of clinical activity.
The Phase I dose escalation trial of ACESOT-1051 (NCT06260514) will accelerate its patient enrollment, with Aprea planning to more than triple its number of active clinical sites for the study from three to 10. The expansion is expected to accelerate the pace of clinical data generation by raising monthly enrollment to between six and 10 patients by the fourth quarter.
By then, Aprea expects to share updated clinical data at a medical meeting for the Phase I trial of APR-1051, an oral, small-molecule inhibitor of WEE1 kinase, a DNA damage response (DDR) pathway protein. WEE1 is designed to regulate the G2 checkpoint, which ensures that cells don’t initiate mitosis until damaged DNA is repaired.
The acceleration aims to help Aprea further characterize the clinical activity of APR-1051 in biomarker-defined tumor populations with a mechanistic rationale for WEE1 inhibition. In addition to accelerating enrollment, Aprea is broadening the development of APR-1051 by advancing it:
- In uterine serous carcinoma (USC) and Cyclin E–overexpressing platinum-resistant ovarian cancer (PROC). Aprea expects to enroll at least 50 patients with USC or PROC.
- Into combination regimens, expanding the Phase I study to include arms enrolling human papillomavirus (HPV)-positive head and neck squamous cell carcinoma and colorectal cancer, in combination with standard-of-care therapies.
In both cases, Aprea said, it will use dose levels for APR-1051 that have shown single-agent activity and cleared safety review. Dose escalation and “backfill” expansion of the patient population is expected to be completed in the second quarter of 2027.
“Our goal is to see who is responding the strongest, who is the most sensitive to our therapy. These are the patient population that we’re going to be then treating in the next phase of development,” Oren Gilad, PhD, Aprea’s president and CEO, told GEN. “In order to de-risk the next phase of development, which is all about overall survival, we are spending lots of time and resources into this stage of the development, into the dose escalation.”
Positive early results
In March, Aprea said a patient with PPP2R1A-mutated endometrial cancer showed confirmed partial response after treatment with a 220 mg dose—a 50% reduction in target lesion size and an 87% decline in CA-125 from 362 at baseline to 47 U/mL. A later assessment showed an additional 9.5% reduction in target lesion size, and a reduction in CA125 from 362 to 40.2U/ml.
And in January, Aprea disclosed positive early results from the study that it said showed early clinical proof-of-concept for APR-1051. A patient with PPP2R1A-mutated uterine serous carcinoma, a form of endometrial cancer, showed a 50% reduction in target lesion size and a >90% reduction in cancer antigen 125 (CA-125) levels, from 732 to 70 U/mL, at the protocol-defined eight-week first imaging assessment after treatment with a 150 mg dose of APR-1051.
Aprea shared clinical data on the uterine cancer patient in “Early results from the first-in-human phase 1 study of WEE1 inhibitor APR-1051 in patients with advanced solid tumors (ACESOT-1051),” a poster presentation at the American Society of Clinical Oncology (ASCO) 2026 Annual Meeting this past spring.
The presentation showed stable disease in six of 28 patients (23%) with advanced solid tumors harboring specific cancer-associated gene alterations, enrolled up to the 300 mg dose level as of the May 6 cutoff. Half (14 of 28) of the enrolled patients had colorectal cancer, followed by uterine/endometrial cancer (eight patients), pancreatic cancer (two), HPV plus HPV-related oropharyngeal squamous cell carcinoma or OPSCC (two), breast cancer (one), and gastric cancer (one).
Preliminary signs of clinical activity were seen in eight patients (29%), consisting of partial responses (two patients) and disease stabilization (six).
“In this study, APR-1051 has shown manageable safety and early signs of tumor shrinkage and no substantial myelosuppression,” researchers concluded in the poster.
Treatment-emergent adverse events (TEAEs) of any grade were reported in 26 of the 28 patients, who had a median of three prior lines of treatments before being dosed with APR-1051. Treatment-related AEs (TRAEs) were reported in 15 patients, with 13 showing non-serious Grade 1 or 2 gastrointestinal events. Two patients had Grade 3 TRAEs consisting of a lymphocyte decrease in one patient (dose level 50 mg) and increased AST and increased ALT in the other patient (a dose-limiting toxicity or DLT, dose level 50 mg).
The one death reported in the poster was due to treatment deemed unrelated to APR-1051.
‘The drug is working’
“When you look at the clinical data, it’s exactly what we were hoping for. We saw tumor shrinkage, and very tolerable side effects,” Gilad said. “The drug is working. It’s doing exactly what it is supposed to be doing. So, the differentiation is that we looked at WEE1 as a target, and WEE1 has been validated to be a good target.”
Gilad and Aprea said APR-1051 holds potential for solving a longtime challenge to treating cancer by targeting WEE1: How to sustain the resulting therapeutic efficacy without achieving harmful side effects in the process? These can include the heavy suppression of bone marrow, which reduces white blood cell production; severe GI distress such as nausea, vomiting, and diarrhea; and systemic fatigue that limits dose size and treatment.
Those effects arose, he said, because earlier WEE1 drugs also inhibited another cell cycle regulatory kinase, Polo-like kinase 1 (PLK). One such dual WEE1/PLK inhibitor, AstraZeneca’s cancer fighting candidate adavosertib (AZD1775), failed a Phase II trial sponsored by the National Cancer Institute (NCT03284385; NCI10170) by failing to exhibit objective response in SETD2-altered clear cell renal cell carcinoma.
Two other Phase II trials of adavosertib were terminated earlier after an interim analysis showed increased toxicity and limited efficacy. One study compared adavosertib plus docetaxel to placebo plus docetaxel in previously treated non-small-cell lung cancer (NSCLC) patients (NCT02087176). The other study compared the effects of adding adavosertib to pemetrexed and carboplatin in patients with previously untreated Stage IV non-squamous NSCLC (NCT02087241).
The trials were among multiple Phase I and II studies whose mixed results prompted AstraZeneca to halt clinical development of adavosertib in 2022.
Back to the drawing board
“There were challenges associated with the other WEE1 inhibitors, because they were not selective, so they became toxic. So, we went back to the drawing board,” Gilad recalled. “PLK inhibitors have been in the clinic. They’re good as single agents, but they also have hem[atological] tox[icity] and they have gut tox, and then you’re adding that on top of the WEE1 inhibition—that’s the one thing we had to resolve. We had to have a WEE1 selective inhibitor, not a WEE1/PLK dual inhibitor.”
“That was our hypothesis, and it seems to be translating pretty nicely to the clinic,” Gilad added. “It’s not that PLK selective inhibitors are not good. They’re good for the patient population that they’re targeting. The argument I’m going to make is that when you’re inhibiting PLK, on top of inhibiting WEE1, It’s not adding; it’s actually taking away.”
Aprea first announced plans to expand the APR-1051 trial on July 31 but restated its expansion plans earlier this month when it reported second quarter earnings. Aprea finished the quarter with a net loss of $3.591 million, about 11% above the $3.239 million net loss of Q2 2025, with no revenue to report during Q2, compared to $118,111 in revenue during Q2 2025.
However, Aprea ended the second quarter with $41.233 million in cash and cash equivalents, nearly triple (up 182%) from $14.599 million in the year-ago quarter. The surge follows the company’s closing on an oversubscribed $30 million private placement during the first quarter, with the proceeds intended to support general corporate purposes as well as R&D expenses for APR-1051 and Aprea’s other lead candidate, ATRN-119 (Mosipasertib).
ATRN-119 is a macrocyclic ATR inhibitor designed for patients with tumors harboring mutations in DDR-related genes. ATRN-119 is being developed as an oral, once-twice-daily treatment for both advanced solid tumors (ovarian, colorectal, and lung) and blood cancers (acute myeloid leukemia, myelodysplastic syndrome).
Last year, Aprea voluntarily paused the Phase I/IIa ABOYA-119 dose-escalation trial of ATRN-119 monotherapy, saying it needed to focus its limited resources on the development of APR-1051.
Talks with academic centers
Aprea said earlier this month it has been in talks with “leading” academic centers to explore studies assessing ATRN-119 in combination with immune-oncology agents, chemotherapy, antibody-drug conjugates (ADCs), and/or radiation.
“Stay tuned,” Gilad said.
Aprea believes its cash and cash equivalents will be able to fund its projected operating expenses and capital expenditure requirements into Q1 2028: “That will definitely, easily take us through completion of dose escalation with enrichment [of the patient population]” for APR-1051, Gilad added.
Over the rest of 2026, he predicted, “we’re going to open more sites. We are opening more sites. So, our rate of enrollment is going to increase, tremendously: More sites, more patients, more data from us—and from others in the field.”
Those others include Zentalis Pharmaceuticals, which in its second quarter update earlier this month announced that it expects to release a topline data readout from Part 2 of its Phase II DENALI trial (NCT05128825) in the first half of 2027—pushed back from the second half of 2026 as the company told investors in May, “to allow for data maturation post full enrollment.”
DENALI is designed to evaluate the efficacy and safety of Zentalis’ azenosertib in patients with PROC, fallopian tube, or primary peritoneal cancer.
“Hopefully they come out with positive data,” Gilad said, “because it’s going to help all patients. It’s going to help everybody.”
