An Open-label, Multi-Center, Phase 2 Clinical Trial Evaluating Sapanisertib and Serabelisib (PIKTOR) With Paclitaxel, and a Substudy Evaluating PIKTOR With Paclitaxel Plus an Insulin-Suppressing Diet, in Patients With Advanced or Recurrent Endometrial Cancer

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Overview

Serabelisib (TAK-117, MLN1117, INK1117; also studied as ART-001) is an investigational oral drug evaluated in cancer and slow-flow vascular malformations. Human phase 1 and phase 2 results are available, but its benefits and risks remain under study. (pmc.ncbi.nlm.nih.gov)

Mechanism of action

Serabelisib selectively inhibits PI3Kα, an enzyme whose catalytic subunit is encoded by PIK3CA. Activating PIK3CA mutations can drive abnormal PI3K signaling in tumors and some vascular malformations. (pmc.ncbi.nlm.nih.gov)

Efficacy

• Slow-flow vascular malformations: In a 35-person phase 2 trial, the proportion with at least a 20% reduction in lesion volume after 24 weeks was 29.4% (5/17) at 50 mg and 33.3% (6/18) at 100 mg. Participants were randomized between two doses, not against a placebo. (pmc.ncbi.nlm.nih.gov)
• Cancer, alone: In a phase 1 trial of advanced solid tumors, 4 of 61 response-evaluable patients had a partial response; 17 had stable disease lasting at least three months. (pmc.ncbi.nlm.nih.gov)
• Cancer, in combinations: A small phase 1 study of serabelisib, sapanisertib and paclitaxel reported 7 responses among 15 evaluable patients (47%); without a control group, the contribution of serabelisib cannot be determined. In a randomized phase 2 kidney-cancer trial, serabelisib plus sapanisertib had a 7.1% response rate, versus 16.7% with everolimus, and did not improve progression-free survival. A phase 2 endometrial-cancer arm combining serabelisib with sapanisertib closed after a futility analysis. (pubmed.ncbi.nlm.nih.gov)

Safety

In the vascular-malformation trial, treatment-emergent adverse events occurred in 82.4% of the 50-mg group and 77.8% of the 100-mg group. Four patients in the 100-mg group had grade 3 or higher drug-related events, chiefly elevated liver enzymes; no drug-related serious adverse events were reported. In the phase 1 cancer monotherapy trial, common adverse events included nausea, vomiting, fatigue and diarrhea; 27% had grade 3 or higher drug-related events, including elevated blood glucose and liver enzymes. Combination regimens have their own toxicity profiles, which cannot be attributed to serabelisib alone. (pmc.ncbi.nlm.nih.gov)

Further reading

• Phase 2 vascular-malformation trial
• First-in-human cancer trial
• Randomized phase 2 kidney-cancer trial
• Phase 1 three-drug combination trial

Last updated: Sep 2026

Overview

Sapanisertib (TAK-228, MLN0128, INK128 or CB-228) is an investigational oral cancer drug studied alone and with other treatments. Human trials have reported responses in some groups, but randomized phase 2 studies have not established a clear benefit over their comparison treatments. (pmc.ncbi.nlm.nih.gov)

Mechanism of action

Sapanisertib blocks the kinase mTOR in both of its signaling complexes, mTORC1 and mTORC2. These complexes help regulate cell growth, metabolism and survival. Unlike drugs that primarily inhibit mTORC1, sapanisertib inhibits the kinase through competition with ATP. (pmc.ncbi.nlm.nih.gov)

Efficacy

• Endometrial cancer: In a randomized phase 2 trial, the response rate was 24.4% with sapanisertib plus paclitaxel versus 18.4% with paclitaxel alone. Median progression-free survival was 5.6 versus 3.7 months, but the difference was not statistically significant; the trial did not meet its primary endpoint. The sapanisertib-alone arm had a 4.9% response rate and closed after a futility analysis. (pmc.ncbi.nlm.nih.gov)
• Renal cell carcinoma: In another randomized phase 2 trial, none of 26 response-evaluable patients receiving sapanisertib alone responded, versus 5 of 30 (16.7%) receiving everolimus. Progression-free survival was not significantly different. (pmc.ncbi.nlm.nih.gov)
• Other cancers: A small phase 2 lung-cancer cohort with NFE2L2-altered squamous tumors had a 25% response rate. In a randomized breast-cancer trial, adding sapanisertib to fulvestrant produced numerically longer progression-free survival, but the investigators did not support further development of those dosing schedules because of toxicity. These findings do not establish benefit across cancers. (pmc.ncbi.nlm.nih.gov)

Safety

Reported adverse effects include hyperglycemia, nausea, vomiting, mouth inflammation, diarrhea and rash. In the endometrial-cancer trial, grade 3 or worse adverse events occurred in 89.5% of patients receiving sapanisertib plus paclitaxel versus 54.0% receiving paclitaxel alone. In the breast-cancer trial, adverse events led to treatment discontinuation in 32%–36% of patients receiving sapanisertib plus fulvestrant, versus 4% receiving fulvestrant alone. (pmc.ncbi.nlm.nih.gov)

Further reading

• Randomized phase 2 endometrial-cancer trial
• Randomized phase 2 renal-cancer trial
• Randomized phase 2 breast-cancer trial
• Phase 1 mechanism and safety study

Last updated: Sep 2026

Inclusion Criteria:

* Histologically confirmed diagnosis of endometrioid endometrial carcinoma.

* Documented evidence of advanced or recurrent endometrial cancer that is not amenable to surgery/radiation for curative intent.

* Participant has received at least 1 but not more than 4 prior systemic therapies. Prior therapy must include platinum-based chemotherapy and a checkpoint inhibitor, either separately or in combination. If a subject has been unable to be treated with checkpoint inhibitor in the past due to medical contraindications, consult with Medical Monitor.

* PI3K/AKT/mTOR pathway gene alteration identified.

* At least 1 measurable target lesion according to RECIST v1.1

* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 at Screening.

* Non-pregnant, non-lactating females who are postmenopausal, surgically sterile or who agree to use effective contraceptive methods..

Exclusion Criteria:

* Participants with central nervous system metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study

* Active malignancy (except for endometrial cancer, definitively treated in-situ carcinomas \[e.g., breast, cervix, bladder\], or basal or squamous cell carcinoma of the skin) within the past 24 months prior to treatment. Fully resected localized malignancies are eligible.

* Gastric feeding tube (gastrostomy tube), gastrointestinal malabsorption, gastrointestinal anastomosis, bowel obstruction, or any other condition that might affect the absorption of study treatment.

* Clinically significant (per Investigator judgement) hemoptysis or tumor bleeding.

* Significant cardiovascular impairment.

* Active, uncontrolled (requiring systemic antimicrobial therapy) infection.

* Concurrent participation in another therapeutic clinical trial.

* Prior radiation therapy within 21 days prior to start of study treatment.

* Strong CYP3A4 inhibitors and inducers are prohibited during the study. Strong CYP1A2 inhibitors as well as CYP1A2 inducers should be administered with caution and at the discretion of the Investigator. Alternative treatments, if available, should be considered. Additionally, strong CYP3A4 inhibitors or inducers should not be taken within 7 days before the first dose of study intervention.

* Participants who require PPIs or chronic use of antacids, histamine H2 receptor blockers, or other treatments to raise gastric pH.

* Prolongation of QTc interval to \>480 ms.

* HbA1c ≥ 8.0% or fasting serum glucose \> 160 mg/dL or fasting triglycerides \> 300 mg/dL or receiving treatment with insulin.