Open-Label Umbrella Study to Evaluate Safety and Efficacy of Sapanisertib and Serabelisib (PIKTOR) in Various Combinations in Patients With HR+/HER2- Advanced or Metastatic Breast Cancer

The study is a Phase 1b/2, multi-center, open-label, dose escalation trial evaluating the safety and preliminary efficacy of sapanisertib and serabelisib (PIKTOR) with fulvestrant and/or other anticancer therapies in participants with HR+/HER2- advanced/metastatic breast cancer.

More details:

The study is a Phase 1b/2, multi-center, open-label, dose escalation trial evaluating the safety and preliminary efficacy of sapanisertib and serabelisib (PIKTOR) with fulvestrant and/or other anticancer therapies in participants with HR+/HER2- advanced/metastatic breast cancer.

Overview

Serabelisib (TAK‑117; MLN1117; INK1117) is an oral, selective phosphoinositide 3‑kinase alpha (PI3Kα) inhibitor investigated in solid tumors, particularly those harboring PIK3CA alterations. A first‑in‑human phase I study (NCT01449370) established intermittent dosing as preferable to continuous daily dosing and reported limited single‑agent activity, prompting development largely in combinations. Combination studies have included sapanisertib (TAK‑228; mTORC1/2 inhibitor) ± paclitaxel and randomized phase 2 trials in endometrial and renal cell carcinoma; results have been mixed to negative, though a small phase I study with paclitaxel reported preliminary activity. A phase 2 trial in advanced/recurrent endometrial cancer combining serabelisib+sapanisertib with paclitaxel (PIKTOR) opened in December 2024. (aacrjournals.org)

Mechanism of action

• Target: Class I PI3K catalytic subunit p110α (PIK3CA). Serabelisib shows >100‑fold selectivity for PI3Kα versus other class I isoforms (β/γ/δ) and mTOR in biochemical assays (IC50 ≈ 21 nM for PI3Kα). Inhibition reduces downstream AKT/mTOR signaling, suppressing proliferation and inducing apoptosis in PIK3CA‑mutant models. Activity is attenuated in PTEN‑deficient or KRAS‑mutant contexts. (aacrjournals.org)
• Immunologic/pharmacology notes: Selective p110α inhibition preserved lymphocyte function relative to pan‑class I PI3K inhibition in preclinical studies. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Single‑agent (Phase I, advanced solid tumors; n=71) - Responses: 4 partial responses across dosing schedules; additional durable stable disease (≥3 months) occurred mainly in patients with PIK3CA‑mutated tumors. Authors concluded single‑agent potential appeared limited. (aacrjournals.org)

Combination with sapanisertib + paclitaxel (Phase I dose‑escalation; NCT03154294) - Population: Heavily pretreated ovarian, endometrial, and breast cancers (n=19). - Activity: CR 3, PR 4, SD >6 months in 4; among 15 evaluable, ORR 47%, clinical benefit rate 73%; median PFS for all 19 reported as 11 months (OS ongoing at 17 months at report). (pubmed.ncbi.nlm.nih.gov) - Earlier ASCO abstract (interim, n=16; 13 evaluable): ORR 46%, CBR 69%, PFS ~10 months. (ascopubs.org)

Randomized studies including a serabelisib arm - Endometrial cancer (Phase 2, four‑arm): Paclitaxel alone; paclitaxel+sapanisertib; sapanisertib alone; sapanisertib+serabelisib. The sapanisertib and sapanisertib+serabelisib arms were closed early for futility; no improvement versus control was observed. (pubmed.ncbi.nlm.nih.gov) - Clear‑cell renal cell carcinoma after VEGF therapy (Phase 2): Sapanisertib±serabelisib vs everolimus. Median PFS 3.8 months (everolimus) vs 3.6 (sapanisertib) vs 3.1 (sapanisertib+serabelisib); no efficacy advantage, and tolerability was worse with sapanisertib±serabelisib. (pubmed.ncbi.nlm.nih.gov)

Ongoing/Planned - PIKTOR phase 2 (advanced/recurrent endometrial cancer): sapanisertib+serabelisib+paclitaxel with an insulin‑suppressing diet substudy; study start December 2024, estimated completion 2029. (clinicaltrials.ucsf.edu)

Safety

Single‑agent serabelisib (Phase I): - Dose‑limiting toxicity with continuous daily dosing was grade ≥3 ALT/AST elevations, leading to a shift to intermittent dosing (MTD 900 mg on intermittent schedules). - Common grade ≥3 treatment‑related AEs included hyperglycemia (up to 15% on some intermittent schedules) and transaminase elevations; overall, intermittent dosing had a more acceptable safety profile. (aacrjournals.org)

Combination with sapanisertib+paclitaxel (Phase I): - Frequent grade 3/4 AEs: decreased WBCs (20%), neutropenia (12%), anemia (9%), hyperglycemia (11%), and elevated liver enzymes (4%); one DLT (renal dysfunction) at highest cohort; dose reductions common at highest cohort. (pubmed.ncbi.nlm.nih.gov)

Randomized settings: - In RCC, discontinuations due to treatment‑emergent AEs were higher with sapanisertib±serabelisib (≈28–29%) versus everolimus (15.6%). (pubmed.ncbi.nlm.nih.gov)

Clinical pharmacology: - Exposure increased with food; proton‑pump inhibitor coadministration (lansoprazole) markedly reduced serabelisib bioavailability in healthy‑volunteer studies, suggesting potential for pH‑dependent absorption interactions. Nausea was common but reduced with food. (accp1.onlinelibrary.wiley.com)

Further reading

• First‑in‑human phase I of serabelisib (Clin Cancer Res, 2017). (aacrjournals.org)
• Phase I sapanisertib+serabelisib+paclitaxel (Gynecol Oncol Rep/Elsevier, 2022) and ASCO 2020 abstract. (pubmed.ncbi.nlm.nih.gov)
• Randomized phase 2 in endometrial cancer including sapanisertib+serabelisib arm (Gynecol Oncol, 2023). (pubmed.ncbi.nlm.nih.gov)
• Randomized phase 2 in RCC: sapanisertib±serabelisib vs everolimus (Oncologist, 2022). (pubmed.ncbi.nlm.nih.gov)
• Preclinical/early AACR abstracts on INK1117 selectivity and activity. (aacrjournals.org)
• Clinical biopharmaceutics (food and gastric pH effects). (accp1.onlinelibrary.wiley.com)
• UCSF PIKTOR phase 2 endometrial cancer trial listing (opened Dec 2024). (clinicaltrials.ucsf.edu)

Notes: Serabelisib remains investigational and is not approved for any indication. Efficacy signals to date have been modest as monotherapy, with selected combination regimens showing preliminary activity but failing to improve outcomes in several randomized phase 2 settings. (aacrjournals.org)

Last updated: Oct 2025

Overview

Sapanisertib (also known as TAK‑228, MLN0128, INK128, CB‑228) is an orally available, ATP‑competitive inhibitor of the mTOR kinase that targets both mTOR complex 1 (mTORC1) and complex 2 (mTORC2). It has been evaluated mainly in phase I–II trials across multiple cancers, often after prior therapy including rapalogs. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Sapanisertib inhibits mTOR’s kinase activity, leading to suppression of downstream signaling (e.g., p-S6K, p‑4EBP1 and AKT Ser473), thereby more completely blocking the PI3K–AKT–mTOR pathway than allosteric mTORC1 inhibitors. Preclinical studies with INK128 (sapanisertib) demonstrate on‑target pathway inhibition and antitumor effects across models. (pubmed.ncbi.nlm.nih.gov)

Efficacy

• Endometrial cancer (randomized phase II): Paclitaxel plus sapanisertib did not significantly improve median PFS versus paclitaxel alone in advanced/recurrent disease (5.6 vs 3.7 months; HR 0.82; p=0.139). In the endometrioid subset, PFS was 5.7 vs 3.3 months (HR 0.66). The sapanisertib-only and sapanisertib+PI3K inhibitor arms were closed for futility. (pubmed.ncbi.nlm.nih.gov)

• Metastatic renal cell carcinoma (single‑arm phase II, heavily pretreated): Objective response rate (ORR) 5.3% (2/38); median PFS 2.5 months. Genomic alterations in MTOR/TSC/PTEN did not correlate with benefit. (ascopubs.org)

• Pancreatic neuroendocrine tumors (phase II, rapalog‑resistant): No objective responses in stage 1; median PFS 5.2 months; study halted for futility per two‑stage design. (pubmed.ncbi.nlm.nih.gov)

• TSC1/TSC2‑mutated metastatic urothelial carcinoma (phase II): Among 13 evaluable patients, no objective responses; trial terminated early for futility. (ascopubs.org)

• HR‑positive/HER2‑negative metastatic breast cancer (phase Ib/II, with endocrine therapy after prior everolimus): Sapanisertib 4 mg QD plus exemestane or fulvestrant achieved clinical benefit rate at 16 weeks (CBR‑16) of 45% in “everolimus‑sensitive” and 23% in “everolimus‑resistant” cohorts; ORR 8% and 2%, respectively. (pubmed.ncbi.nlm.nih.gov)

Safety

Across studies, the most frequent adverse events include gastrointestinal toxicities (nausea, diarrhea, stomatitis), rash, fatigue/asthenia, and on‑pathway metabolic effects (notably hyperglycemia and hypertriglyceridemia). Dose‑limiting toxicities commonly involve hyperglycemia, rash, stomatitis, and fatigue. Maximum tolerated doses in early studies included 3–6 mg once daily (schedule‑dependent) or 30–40 mg once weekly; 4 mg once daily was the recommended dose in several combinations. (pubmed.ncbi.nlm.nih.gov)

Dosing/schedules explored

Multiple schedules have been investigated: - Continuous once‑daily dosing (e.g., 3–6 mg QD); intermittent QD 3 days‑on/4 days‑off or 5 days‑on/2 days‑off; and once‑weekly dosing (30–40 mg). Food reduces Cmax but not overall exposure. Combination dosing commonly used 4 mg QD. (pubmed.ncbi.nlm.nih.gov)

Interpretation

As a dual mTORC1/2 inhibitor, sapanisertib has shown biological activity and manageable but characteristic on‑target toxicities. Thus far, single‑agent efficacy signals in unselected, heavily pretreated solid tumors have been limited, and biomarker‑selected settings (e.g., TSC1/2‑mutant urothelial carcinoma) have not yet demonstrated clear benefit. Combination approaches (e.g., with endocrine therapy after prior everolimus) have shown modest activity in specific contexts, meriting further investigation. (ascopubs.org)

Further reading

• Phase I solid tumor dose‑finding and schedules: Kristeleit et al., 2020. (pubmed.ncbi.nlm.nih.gov)
• Randomized phase II in endometrial cancer (paclitaxel ± sapanisertib): 2023. (pubmed.ncbi.nlm.nih.gov)
• Phase II in metastatic RCC: JCO Precision Oncology, 2022. (ascopubs.org)
• Rapalog‑resistant PNETs (EA2161): 2022. (pubmed.ncbi.nlm.nih.gov)
• HR+/HER2− metastatic breast cancer with endocrine therapy: Clinical Cancer Research, 2021. (pubmed.ncbi.nlm.nih.gov)
• Early combinations (e.g., with paclitaxel ± trastuzumab): 2017. (pubmed.ncbi.nlm.nih.gov)

Notes: Synonyms include TAK‑228, MLN0128, INK128, and CB‑228. Mechanistic and preclinical background on ATP‑competitive mTORC1/2 inhibition with INK128 are available in peer‑reviewed studies. (aacrjournals.org)

Last updated: Oct 2025

Inclusion Criteria:

* Histologically confirmed diagnosis of HR+/HER2- breast cancer.

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

* Participant has received at least one prior systemic therapy.

* At least 1 measurable or evaluable 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 triple-negative breast cancer.

* 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 breast 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.

* Significant cardiovascular impairment.

* Active, uncontrolled infection.

* Concurrent participation in another therapeutic clinical trial.

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

* Participants who have received a prior PI3K, AKT, mTORC1/2, or dual PI3K/mTOR inhibitor.

* Strong CYP3A4 inhibitors, strong CYP1A2 inhibitors or CYP1A2 inducers, or clinically significant CYP3A4 inducers within 7 days before the first dose of study intervention, or participants who require treatment with strong CYP3A4 inhibitors or inducers during the study.

* Prolongation of QTc interval to \>480 ms.

* Type 1 or Type 2 diabetes mellitus on insulin.