samotolisib (LY3023414)

P2, N=130, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Aug 2030 | Trial primary completion date: Aug 2026 --> Aug 2027

This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.

Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.

P2, N=130, Recruiting, Dana-Farber Cancer Institute | N=60 --> 130 | Trial completion date: May 2026 --> Aug 2029 | Trial primary completion date: May 2024 --> Aug 2026

P1, N=198, Active, not recruiting, Eli Lilly and Company | Phase classification: P1b --> P1

We have provided proof of concept for two preclinical anal cancer treatment models that allow for the future testing of novel therapies for anal cancer.

In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.

P1b, N=198, Active, not recruiting, Eli Lilly and Company | Trial completion date: Sep 2023 --> Dec 2024

P2, N=18, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Sep 2024 --> Sep 2023

P2, N=10, Completed, Baylor Research Institute | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Nov 2022

P2, N=24, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=10, Active, not recruiting, Baylor Research Institute | Trial completion date: Dec 2022 --> Dec 2023

P2, N=60, Recruiting, Dana-Farber Cancer Institute | N=40 --> 60 | Trial completion date: May 2025 --> May 2026 | Trial primary completion date: May 2023 --> May 2024

A panel of PrC cell lines with different PI3K or PTEN status (wt: 22RV1, MDA-PCa-2b, DU145; null: LNCaP, PC3, C4-2) were assayed under different conditions for their sensitivity to gedatolisib and other PAM-I (PI3K: alpelisib, copanlisib; AKT: capivasertib, ipatasertib; mTOR: everolimus; pan-PI3K/mTOR: samotolisib, gedatolisib). We demonstrated that gedatolisib exerts superior activity regardless of PI3K or PTEN status in all PrC cell lines evaluated compared to the other PAM pathway inhibitors evaluated. Our results indicate potent and simultaneous blockade of all Class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN dependent resistance. Gedatolisib as a single agent and in combination with other therapies reported promising preliminary efficacy and safety in various solid tumor types.

By contrast, pretreatment with the STAT3 inhibitor C188-9 or the PI3K/AKT/mTOR inhibitor LY3023414 reversed the LIF-induced inhibition of RGC loss. These results suggested that exogenous LIF treatment inhibited the retinal damage induced by AOH, which was associated with the activation of STAT3 and mTOR/p70S6K signaling. Therefore, LIF may serve a role in neuroprotection for glaucoma treatment.

P2, N=10, Active, not recruiting, Baylor Research Institute | Trial completion date: Aug 2022 --> Dec 2022

Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone and this may be enriched in patients with PTEN intact and no AR-v7.

P2, N=10, Active, not recruiting, Baylor Research Institute | Recruiting --> Active, not recruiting

P2, N=24, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P2, N=24, Suspended, National Cancer Institute (NCI) | N=144 --> 24

P1, N=156, Completed, Eli Lilly and Company | Active, not recruiting --> Completed

P2, N=31, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2022 --> Mar 2022 | Trial primary completion date: Sep 2022 --> Mar 2022

Combination index and Bliss independence analyses indicated that inhibition of OS growth by exposure to CDK4/6i (Palbociclib or Abemaciclib) and PI3K/mTOR inhibitor (PI3K/mTORi-Voxtalisib or LY3023414) was additive-to-synergistic and lead to increased apoptosis at clinically relevant concentrations. Notably, Palbociclib + Voxtalisib was more efficacious than single-agent (p<0.05, Two-way ANOVA; Holm-Sidak). These data highlight the need to optimize CDK4/6i+PI3K/mTORi dosing schedules and provide evidence that Palbociclib + Voxtalisib therapy is safe, efficacious, and can decrease CDK4/6i resistance in aggressive PDX models of OS.

P2, N=2316, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P2, N=144, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1b, N=198, Active, not recruiting, Eli Lilly and Company | Trial completion date: Oct 2022 --> Oct 2023

Dual PI3K/mTOR (LY3023414, bimiralisib) and AKT inhibitors (ipatasertib, afuresertib) induced dose-dependent reductions in cell growth. However, mTOR-selective inhibitors (everolimus, rapamycin) alone did not exert cytotoxic effects. The MEK1/2 inhibitor trametinib did not impact proliferation even at the highest doses tested. Our data suggest that molecularly targeted strategies may be effective in PI3K/AKT/mTOR-activated ssRMS. Taken together, these data highlight the importance of utilizing patient-derived models to assess molecularly targetable treatments and their potential as future treatment options.

P1, N=156, Active, not recruiting, Eli Lilly and Company | Trial completion date: Oct 2021 --> Jan 2022

P2, N=2316, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P2, N=2316, Recruiting, National Cancer Institute (NCI) | N=1500 --> 2316

P1, N=156, Active, not recruiting, Eli Lilly and Company | Trial completion date: Mar 2021 --> Oct 2021

Combined therapy of PI3K/mTOR dual inhibitor LY3023414 and carboplatin had synergistic anti-tumor effects in EC cell line and some of the PDX EC models, without increasing the toxicity of single drug. Enhanced carboplatin-induced DNA damage response (DDR) and cell apoptosis may be the mechanisms of synergistic effects. The anti-tumor effects may correlate with the mutational pattern of PI3K pathway, which provides experimental basis of individual treatments of ECs in the future.

P2, N=31, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2021 --> Sep 2022 | Trial primary completion date: Sep 2021 --> Sep 2022

The novel PIK3CA p.I459_T462del mutation is not a catalytically activating mutation, and the GNASp.R201C mutation does not activate the MAPK pathway in murine myoblast lineage cells. While LY3023414 and rapamycin biochemically inhibited the PI3K/AKT pathway significantly, single drug agents did not result in cell death. However, combination therapy involving LY3023414 with doxorubicin and rapamycin with vincristine showed synergistic effect.

P2, N=10, Recruiting, Baylor Research Institute | Trial completion date: Aug 2021 --> Aug 2022 | Trial primary completion date: Jun 2021 --> Jun 2022

The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.

CONCLUSION LY3023414 monotherapy (200 mg BID) demonstrated an acceptable and manageable safety profile with limited single-agent activity in patients with advanced mesothelioma. ClinicalTrials.gov identifier: NCT01655225; Date of registration: 19 July 2012.

RAS gene mutations are the most frequent oncogenic event in lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and - equally important - to identify biomarkers for patient stratification.

Prexasertib+samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily-pretreated patients. The clinical combination was associated with toxicity, suggesting supportive measures may be required. However, these data may inform future trials using other CHK1 and PI3K pathway inhibitors.

In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile.

We thus conducted a high throughput drug combination screening of a CHK1i, prexasertib (Prex) with 1,912 drugs in HGSOC cell lines (BRCA wild-type [BRCAwt: OVCAR5 and OVCAR8] and BRCA2 mutant [BRCA2m: PEO1])...We confirmed the combination of Prex and a dual PI3K/mTOR inhibitor LY3023414 (LY302) yielded synergistic cytotoxicity (combination index<1) in a panel of HGSOC cell lines (OVCAR3, OVCAR5, OVCAR8, OV90 and PEO4 [all BRCA-proficient] and PEO1) by XTT and colony formation assays...Supporting this notion, Prex+LY302 augmented RS as evidenced by increased phospho-RPA+/γH2AX+ populations compared with Prex (increased 37% and 38%, respectively; P<0.05) or LY302 (increased 80% and 79%, respectively; P<0.001). Overall, our results suggest that dual inhibition of CHK1 and PI3K pathways results in greater RS, DNA damage and subsequent cell death in HGSOC cells independent of BRCA mutation status.