ipatasertib (RG7440)

P2, N=175, Active, not recruiting, German Cancer Research Center | Recruiting --> Active, not recruiting

Chaperonin TCP1 subunit 6A (CCT6A) plays an oncogenic role in triple-negative breast cancer (TNBC) through the AKT signaling pathway. TRIM21 facilitated K48-linked ubiquitination-mediated degradation of CCT6A, thereby impeding TNBC progression. Our study collectively underscores the potential of Ipatasertib in conjunction with anti-PD1 therapy as a promising strategy to counteract CCT6A/AKT hyperactivity-driven TNBC progression.

P1, N=20, Terminated, Hoffmann-La Roche | Phase classification: P3 --> P1

We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT)...Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin...In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers.

TAKTIC was a phase Ib open-label trial evaluating ipatasertib in combination with fulvestrant, an aromatase inhibitor, or fulvestrant + palbociclib, in participants with HR+/HER2- MBC who received ≥1 line of prior therapy for MBC and had exposure to CDK4/6i (NCT03959891). Genomic insights using NGS suggest that MBC post-CDK4/6i is more susceptible to an AKTi-based treatment with ipatasertib in the presence of a PI3K/AKT/PTEN pathway mutation, whereas alterations in FGFR1 are associated with worse outcomes. This effort is one of very few studies prospectively evaluating mediators of AKTi response, an area of active interest given changes in the therapeutic landscape. The results presented here are hypothesis-generating; future work is underway to further expand upon these data.

P1/2, N=138, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Ipatasertib+paclitaxel demonstrated more encouraging activity. The tolerability of both regimens was consistent with previous experience.

Recent approvals and ongoing investigations of single agents and intensification approaches will keep transforming the mCRPC treatment landscape. Improvement of patient profiling applying recognized genomic, molecular, and clinical predictive and prognostic indicators is fundamental to optimize sequential use of available therapies.

P2, N=176, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2028 --> May 2028 | Trial primary completion date: May 2028 --> Feb 2028

Furthermore, over fifty of the impacted proteins represent approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Altogether, the exposure of SKBR3/HER2+ cells to Lapatinib and Ipatasertib kinase inhibitors uncovered a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ERBB2 and PI3K/AKT pathways.

P1/2, N=138, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2024 --> Sep 2024

P1/2, N=138, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Dec 2024 --> Sep 2024

P1/2 | N=580 | Recruiting | Sponsor: Hoffmann-La Roche | N=242 ➔ 580 | Trial completion date: May 2026 ➔ May 2028 | Trial primary completion date: May 2026 ➔ May 2028

P2 | "The most frequently assigned TTs were IPI/NIVO (37%), ipatasertib (16%), pemigatinib (8%), TDM1 (8%), and atezo/ipatasertib (6%). The incidence of G≥3 AEs was 35% for TT and 40% for SoC. Conclusions The ROME Trial demonstrated that a mutational-based treatment approach based on the MTB discussion of CGP results may significantly improve ORR and PFS compared to SoC in pretreated patients with metastatic solid tumors, particularly with immunotherapy."

P3, N=250, Active, not recruiting, Canadian Cancer Trials Group | Trial primary completion date: Jun 2024 --> Dec 2024

Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood.

P1, N=24, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Jan 2025 | Trial primary completion date: Jun 2024 --> Jan 2025

We initially confirmed that the PLK1 specific inhibitor onvansertib (ONV) could enhance responses to a PARP inhibitor (olaparib) in prostate cancer xenografts...We confirmed in vitro synergy between ONV and the AKT inhibitor ipatasertib (IPA) and found that the combination increased apoptosis...Studies in three PTEN deficient prostate cancer xenograft models showed that co-treatment with IPA and ONV led to significant tumor growth inhibition compared to monotherapies. Together these in vitro and in vivo studies demonstrate that the efficacy of PLK1 antagonists can be enhanced by PARP or AKT inhibition, and support further development of these combination therapies.

P2; Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Aug 2023 | Trial primary completion date: Dec 2022 --> Aug 2023

P2, N=528, Active, not recruiting, Hoffmann-La Roche | N=790 --> 528

For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation...Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins...Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins within the RAS upstream and downstream signaling pathways in cancer.

P3, N=1101, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P2, N=52, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jun 2025 | Trial primary completion date: Jul 2024 --> Jun 2025

P1/2, N=675, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Jun 2026 --> Sep 2025 | Recruiting --> Active, not recruiting | Trial completion date: Sep 2027 --> Nov 2026

P2, N=176, Active, not recruiting, Hoffmann-La Roche | N=550 --> 176

P3, N=250, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P2 | "Clinical Trial Registration Number: NCT04589845"

Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) as monotherapy or when combined with the VEGF-targeted tyrosine kinase inhibitor, lenvatinib, have demonstrated promising response rates in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively...Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity in relapsed recurrent EC, and other solid tumors (e.g. NSCLC, HCC) as monotherapy and as part of combinatorial therapy...In AFT-50A, pts may be eligible for one of the following doublets: Atezo+talazoparib (tumors with genomic loss of heterozygosity (gLOH ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB-H). The Atezo+bevacizumab (biomarker unmatched) and Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered tumors) cohorts have completed accrual...AFT-50B pts will be eligible for inavolisib (PIK3CAm/PTEN and AKT1wt-altered tumors) + letrozole or giredestrant + abemaciclib (RB1wt, estrogen receptor positive tumors)...As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 20 sites in the US with a target of 25 sites nationwide.

P2, N=550, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P3, N=20, Terminated, Hoffmann-La Roche | Completed --> Terminated; The decision to not open the Phase III portion was based on a strategic sponsor decision and not driven by any safety concerns.

P2, N=252, Completed, Genentech, Inc. | Active, not recruiting --> Completed

P3, N=1101, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2023 --> Apr 2024

A growth inhibition screen with 288 cancer cell lines confirmed that INY-05-040 had a substantially higher potency than our first-generation AKT degrader (INY-03-041), with both compounds outperforming catalytic AKT inhibition by GDC-0068...Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low basal JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Together, our study presents a framework for mapping the network-wide signaling effects of therapeutically relevant compounds and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling.

P2, N=200, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting | N=600 --> 200

P1/2, N=96, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P1/2, N=28, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Sep 2023

P2, N=600, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=675, Recruiting, Hoffmann-La Roche | N=470 --> 675 | Trial completion date: Nov 2026 --> Sep 2027 | Trial primary completion date: Aug 2025 --> Jun 2026

Approximately, 30% of recurrent EC pts fall into this category. Pairing ICI with targeted therapies carries the potential to elicit prolonged anti-tumor effects. Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC...In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB>10 mut/MB). The Atezo+bevacizumab (biomarker unmatched) arm is closed to enrollment...Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months...As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 18 sites in the US with a target of 25 sites nationwide.

The average binding free energies for the Akt1-CQU, Akt1-Ipatasertib, and Akt1-Hit9 systems were - 34.44, - 63.37, and - 39.14 kJ mol, respectively. In summary, the results obtained in this investigation suggested that Hit9 with novel scaffold may be a promising lead compound for developing new Akt1 inhibitor for treatment of various cancers with Akt1 overexpressed.

In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.