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) is an investigational, oral, PI3Kα-selective inhibitor developed for advanced solid tumors. Early monotherapy evaluation showed limited single‑agent activity, prompting exploration primarily in combinations, including with the dual mTORC1/2 inhibitor sapanisertib and chemotherapy. No regulatory approvals are reported as of September 2, 2025. (pmc.ncbi.nlm.nih.gov, ckb.genomenon.com)

Mechanism of action

• Target: Class I PI3K catalytic subunit p110α (PIK3CA). In biochemical assays, serabelisib inhibits PI3Kα with an IC50 around 21 nM and is >100‑fold selective over PI3Kβ/γ/δ and mTOR. In PIK3CA‑mutant models, it suppresses PI3K signaling (e.g., pAKT/pS6), inhibits proliferation, and can induce apoptosis. (pmc.ncbi.nlm.nih.gov)
• Pharmacokinetics/dosing explored: Oral administration with a terminal half‑life of ~11 hours; intermittent 3‑days‑per‑week schedules (e.g., M‑W‑F or M‑Tu‑W) enabled higher weekly exposure and improved tolerability versus continuous daily dosing in phase I studies. (pmc.ncbi.nlm.nih.gov)

Efficacy

Monotherapy (phase I, advanced solid tumors) - In a first‑in‑human dose‑escalation study (n=71 treated; 61 response‑evaluable), objective responses occurred in 4 patients (all PIK3CA‑mutant; 3 breast, 1 gastric); 28% had stable disease ≥3 months. Authors concluded single‑agent activity was limited. (pmc.ncbi.nlm.nih.gov)

Combination therapy

• Serabelisib + sapanisertib + paclitaxel (phase I/Ib in heavily pretreated ovarian, endometrial, or breast cancers; NCT03154294): Among 15 evaluable patients, ORR was 47% (3 complete responses, 4 partial responses); clinical benefit rate 73%; reported median PFS ~11 months. Small, nonrandomized study. (pubmed.ncbi.nlm.nih.gov, ascopubs.org, gynecologiconcology-online.net)

• Sapanisertib ± serabelisib vs everolimus (randomized phase II, advanced clear‑cell renal cell carcinoma; n=95): Adding serabelisib to sapanisertib did not improve outcomes versus everolimus. Median PFS was 3.8 months (everolimus) vs 3.6 (sapanisertib) and 3.1 (sapanisertib+serabelisib); ORR 16.7%, 0%, and 7.1%, respectively. (pmc.ncbi.nlm.nih.gov)

Ongoing development - A phase 2 program is evaluating serabelisib+sapanisertib with paclitaxel in recurrent/advanced endometrial cancer, including randomized designs; status includes recent site listings and study postings (PIK‑201/GOG‑3111; NCT06463028). Results are pending. (clinicaltrials.ucsf.edu, inclinicaltrials.com, centerwatch.com)

Safety

Monotherapy (phase I) - Dose‑limiting toxicities on continuous daily dosing included grade ≥3 ALT/AST elevations; intermittent dosing reduced hepatotoxicity at comparable weekly exposure. Common treatment‑related grade ≥3 events included hyperglycemia (up to 15% on intermittent schedules). (pmc.ncbi.nlm.nih.gov)

Combination therapy - Triplet with sapanisertib and paclitaxel: Most frequent grade 3/4 adverse events included decreased WBCs (20%), neutropenia (12%), anemia (9%), hyperglycemia (11%), and elevated liver enzymes (4%); one DLT reported at the highest cohort. Overall tolerability considered acceptable in early cohorts. (pubmed.ncbi.nlm.nih.gov) - Randomized RCC study (sapanisertib ± serabelisib vs everolimus): Combination arms were less tolerable; discontinuations due to treatment‑emergent AEs occurred in 28–29% with sapanisertib±serabelisib vs 15.6% with everolimus. Common AEs with combinations included nausea, vomiting, fatigue, and diarrhea. (pmc.ncbi.nlm.nih.gov)

Further reading

• Juric et al. First‑in‑human phase I of serabelisib (mechanism, PK/PD, single‑agent activity). Clin Cancer Res 2017. (pmc.ncbi.nlm.nih.gov)
• Starks et al. Phase I serabelisib+sapanisertib+paclitaxel in ovarian/endometrial/breast cancer (ORR/CBR data). Gynecol Oncol 2022; plus ASCO 2020 meeting abstract. (pubmed.ncbi.nlm.nih.gov, ascopubs.org)
• Ornstein et al. Randomized phase II in ccRCC: sapanisertib ± serabelisib vs everolimus (no efficacy advantage; safety). Oncologist 2022. (pmc.ncbi.nlm.nih.gov)
• Food/pH PK study design details for TAK‑117 formulation (healthy volunteer crossover). (trial.medpath.com, ctv.veeva.com)
• PIKTOR endometrial cancer phase 2 program overview and listings (NCT06463028). (clinicaltrials.ucsf.edu, centerwatch.com)

Notes: Serabelisib remains investigational; reported efficacy derives from early‑phase or disease‑specific studies with limited sample sizes, and combination‑strategy results have been mixed across indications. (pmc.ncbi.nlm.nih.gov, pubmed.ncbi.nlm.nih.gov)

Last updated: Sep 2025

Overview

Sapanisertib (also known as TAK‑228, MLN0128, INK128, CB‑228) is an oral, investigational, ATP‑competitive inhibitor of the mTOR kinase that targets both mTOR complex 1 and 2 (mTORC1/2). It has been evaluated across multiple tumor types as monotherapy and in combinations. Early signals of activity have been described in NRF2‑mutated squamous non–small cell lung cancer (sqNSCLC), and the agent received FDA Fast Track designation for this population in 2022; however, across several other settings single‑agent activity has generally been limited. (healio.com, targetedonc.com)

Mechanism of action

• Catalytic, ATP‑competitive inhibitor of mTOR that suppresses signaling downstream of both mTORC1 and mTORC2, inhibiting phosphorylation of 4EBP1/S6K (mTORC1) and AKT S473 (mTORC2). This dual blockade can prevent feedback reactivation of AKT seen with rapalogs. (pubmed.ncbi.nlm.nih.gov, pmc.ncbi.nlm.nih.gov)
• Preclinical models showed broad antiproliferative and antitumor effects across sarcoma and RCC, with greater suppression of tumor growth and metastases than rapamycin/temsirolimus and inhibition of 4EBP1, S6K1, HIF1α, and AKT phosphorylation. (pubmed.ncbi.nlm.nih.gov, pmc.ncbi.nlm.nih.gov)

Efficacy

Renal cell carcinoma (RCC) - Single‑arm phase 2 (weekly sapanisertib 30 mg) in treatment‑refractory metastatic RCC (NCT03097328): ORR 5.3% (2/38), median PFS 2.5 months (95% CI 1.8–3.7); minimal activity irrespective of mTOR‑pathway alterations. (ascopubs.org) - Phase 1 dose‑escalation/expansion across schedules: preliminary antitumor activity with 1 CR and 9 PRs overall (most in RCC/endometrial cancer). MTDs included 6 mg QD and 40 mg QW; recommended expansion doses were 5 mg QD or 30 mg QW. (pubmed.ncbi.nlm.nih.gov)

Endometrial cancer - Randomized phase 2 (paclitaxel vs paclitaxel+sapanisertib; separate single‑agent arms):
- Combination arm showed higher clinical benefit rate (CBR 80.2% vs 57.5%) and ORR 24.4% vs 18.4% (not statistically significant for ORR); single‑agent sapanisertib and sapanisertib+PI3K inhibitor (TAK‑117/serabelisib) arms were closed at interim analysis for low activity (CBR‑16 17.1% and 5.0%, respectively). (pmc.ncbi.nlm.nih.gov)

Pancreatic neuroendocrine tumors (pNET), rapalog‑resistant - Two‑stage phase 2 (EA2161): no objective responses at interim analysis; disease control rate 66.7%, median PFS 5.19 months; study halted for futility. (pmc.ncbi.nlm.nih.gov)

Acute lymphoblastic leukemia (ALL) - Single‑arm phase 2 (3 mg QD, 21/28 days): no CR/CRi; best response stable disease in 12.5–19% depending on reporting; limited target inhibition on serial samples. (pmc.ncbi.nlm.nih.gov, pubmed.ncbi.nlm.nih.gov)

Lung cancer (NRF2‑mutated sqNSCLC) - Early phase 2, investigator‑initiated: confirmed ORR 25–27% (3/11 or 3/12) and median PFS 8.9 months in heavily pretreated NRF2‑mutated sqNSCLC; data primarily reported in conference/press summaries. FDA granted Fast Track designation based on this signal; a randomized phase 2 is ongoing (NCT05275673). (jto.org, healio.com, targetedonc.com, biospace.com)

Combination studies (early phase) - With paclitaxel ± trastuzumab (phase 1): PRs in 8/54 evaluable patients; suggested feasibility across intermittent dosing schedules. (pubmed.ncbi.nlm.nih.gov) - With paclitaxel and serabelisib (phase 1): ORR 47% and CBR 73% among 15 evaluable, heavily pretreated patients (ovarian/endometrial/breast); exploratory, small cohort. (pubmed.ncbi.nlm.nih.gov) - With carboplatin+paclitaxel in mTOR‑altered tumors (phase 1): PR in 2/17 evaluable; disease control 68%; median PFS 3.84 months. (pmc.ncbi.nlm.nih.gov, pubmed.ncbi.nlm.nih.gov)

Safety

Across studies, the safety profile is consistent with mTOR‑pathway inhibition: - Common adverse events: hyperglycemia, stomatitis/mucositis, rash, diarrhea, nausea, fatigue, decreased appetite; myelosuppression when combined with chemotherapy. Grade ≥3 AEs included hyperglycemia, diarrhea, neutropenia, anemia, and stomatitis depending on regimen/schedule. (pubmed.ncbi.nlm.nih.gov, pmc.ncbi.nlm.nih.gov) - In refractory mRCC (weekly dosing), 32% had treatment‑related grade 3 AEs; no grade 4/5 toxicities reported. (ascopubs.org) - Cardiac repolarization: a dedicated phase 1 QT study found no clinically meaningful QTc prolongation with a single 40‑mg dose; weekly 30‑mg dosing showed a favorable cardiac safety profile. (pmc.ncbi.nlm.nih.gov) - Notable but less frequent events: pneumonitis was observed in one patient in an ALL phase 2; neurologic AEs (seizures/confusion) were rare. (pmc.ncbi.nlm.nih.gov)

Further reading

• Mechanism/preclinical
• MLN0128 inhibits mTORC1/2 and prevents feedback AKT activation; antitumor activity in sarcoma models. (pubmed.ncbi.nlm.nih.gov)
• MLN0128 superior to temsirolimus in RCC tumorgraft models; dual pathway inhibition confirmed. (pmc.ncbi.nlm.nih.gov)
• Clinical trials
• Phase 1 dose‑escalation/expansion in solid tumors (schedules, MTDs, preliminary activity). (pubmed.ncbi.nlm.nih.gov)
• Phase 2, refractory mRCC (single‑agent; limited activity). (ascopubs.org)
• Randomized phase 2 in endometrial cancer (paclitaxel ± sapanisertib; single‑agent arms closed for futility). (pmc.ncbi.nlm.nih.gov)
• Phase 2 in rapalog‑resistant pNET (no responses; modest disease control). (pmc.ncbi.nlm.nih.gov)
• Phase 2 in ALL (no CR/CRi; limited efficacy; pharmacodynamic data). (pmc.ncbi.nlm.nih.gov)
• NRF2‑mutated sqNSCLC: early phase 2 signal and FDA Fast Track designation; ongoing randomized phase 2. (jto.org, healio.com)

Notes: Most positive lung cancer data are from small, early experiences and conference/press materials; confirmatory studies are ongoing.

Last updated: Sep 2025

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.