Delving into the Latest Updates on LY-2780301 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

Akt-1 inhibitors(Serine/threonine-protein kinase AKT inhibitors), RSK inhibitors(Ribosomal protein S6 kinase inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesImmune System Diseases+ [1]

Active Indication-

Inactive Indication

Locally advanced breast cancerMetastatic breast cancerNeoplasm Metastasis+ [2]

Originator Organization

Eli Lilly & Co.

Active Organization-

Inactive Organization

Institut Jean Paoli & Irene Calmettes

Eli Lilly & Co.Gustave Roussy, Cancer Campus, Grand Paris

Drug Highest PhaseDiscontinuedPhase 1/2

First Approval Date-

Regulation-

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The overall rationale of this study evaluating tolerance and efficacy of LY2780301 in combination with paclitaxel in HER2-negative, inoperable locally advanced or metastatic breast cancer (MBC) is based on :
the medical need in this population with either hormonal-resistant or unsensitive and/or rapidly progressive disease
the preclinical evidences for involvement of PI3K/AKT pathway in tumor progression and drug resistance, including taxanes as well as its potential reversion by AKT inhibition
the high level of frequency of PI3K/AKT activation in HER2-negative MBC
the in vitro and in vivo preclinical activity of LY2780301, and its synergistic combination with various anticancer agents, including taxanes
the favourable profile of tolerance of LY2780301 in phase I trial
Weekly paclitaxel is conventionally administered at 80 mg/m²/week and is a standard treatment in breast cancer (BC) As described above, LY2780301 500 mg once daily has been established as the RP2D in phase I single agent trial.
Evidence of pharmacodynamic activity was noted at 400-500 mg QD. Conservatively, the first dose level to be explored will be LY2780301 400 mg QD and paclitaxel 70 mg/m²/week.

Start Date01 Jan 2014

Sponsor / Collaborator

Institut Jean Paoli & Irene Calmettes

NCT02018874 / CompletedPhase 1IIT

A Phase Ib, Open-label, Dose Escalation Study of the Safety, Tolerability and Efficacy of LY2780301 (a p70/AKT Inhibitor) in Combination With Gemcitabine in Patients With Advanced or Metastatic Cancer

In the First-in-Human, JWAA trial, the LY2780301 displayed a favourable safety profile, a high pharmacokinetic exposure and the ability to decrease pS6. LY2780301 has shown synergistic activity in combination with targeted agents or chemotherapy including gemcitabine. We propose herein to combine LY2780301 with gemcitabine and to treat different tumor types with molecular alterations. This may validate the anti-tumor activity of the LY2780301 and it will increase our knowledge regarding molecular predictors of its efficacy.

Start Date01 Sep 2013

Sponsor / Collaborator

Gustave Roussy, Cancer Campus, Grand Paris

NCT01115751 / CompletedPhase 1

A Phase I Trial of Single-Agent LY2780301 in Patients With Advanced or Metastatic Cancer

Study JWAA is a multicenter, nonrandomized, open-label, dose-escalation Phase 1 study of oral LY2780301 in patients with advanced solid tumors.

Start Date01 Mar 2010

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with LY-2780301

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100 Translational Medicine associated with LY-2780301

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100 Patents (Medical) associated with LY-2780301

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5

Literatures (Medical) associated with LY-2780301

01 May 2022·Molecular OncologyQ2 · MEDICINE

Circulating tumor DNA predicts efficacy of a dual AKT/p70S6K inhibitor (LY2780301) plus paclitaxel in metastatic breast cancer: plasma analysis of the TAKTIC phase IB/II study

Q2 · MEDICINE

ArticleOA

Author: Adelaïde, José ; Goncalves, Anthony ; Pakradouni, Jihane ; Dalenc, Florence ; Garnier, Séverine ; Isambert, Nicolas ; Bertucci, François ; Robert, Marie ; Mamessier, Emilie ; Chaffanet, Max ; Vicier, Cécile ; Guille, Arnaud ; Levy, Christelle ; Sfumato, Patrick ; Sabatier, Renaud ; Carbuccia, Nadine

The phosphatidylinositol‐3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in HER2‐negative breast cancer and may play a role in taxane resistance. The phase IB/II TAKTIC trial (NCT01980277) has shown that combining a dual AKT and p70 ribosomal protein S6 kinase (p70S6K) inhibitor (LY2780301) taken orally with weekly paclitaxel in HER2‐negative advanced breast cancer is feasible, with preliminary evidence of efficacy. We wanted to explore whether circulating tumor DNA (ctDNA) may be a surrogate marker of treatment efficacy in this setting. Serial plasma samples were collected and cell‐free DNA was sequenced using low‐coverage whole‐genome sequencing, and analysis was completed with droplet digital polymerase chain reaction (PCR) for some patients with driver mutations. Baseline tumor fraction (TF) and TF after 7 weeks on treatment were compared to progression‐free survival (PFS) and the overall response rate. We also explored circulating copy number alterations associated with treatment failure. Of the 51 patients enrolled in the TAKTIC trial, at least one plasma sample was available for 44 cases (96 timepoints). All patients with tumor TP53, PI3KCA, or AKT1 mutations harbored at least one of these alterations in plasma. TF at inclusion was correlated with PFS (6m‐PFS was 92% for ctDNAneg patients vs 68% for ctDNApos cases; hazard ratio [HR] = 3.45, 95% confidence interval [CI] [1.34–8.90], P = 0.007). ctDNA status at week 7 was not correlated with prognosis. Even though most circulating copy number alterations were conserved at disease progression, some genomic regions of interest were altered in post‐progression samples. In conclusion, ctDNA detection at baseline was associated with shorter PFS in patients included in the TAKTIC trial. Plasma‐based copy number analysis may help to identify alterations involved in resistance to treatment.

01 Dec 2021·European Journal of CancerQ1 · MEDICINE

TAKTIC: A prospective, multicentre, uncontrolled, phase IB/II study of LY2780301, a p70S6K/AKT inhibitor, in combination with weekly paclitaxel in HER2-negative advanced breast cancer patients

Q1 · MEDICINE

Article

Author: Robert, Marie ; Pakradouni, Jihane ; Sabatier, Renaud ; Boher, Jean M ; Gonçalves, Anthony ; Sfumato, Patrick ; Garnier, Séverine ; Charafe-Jauffret, Emmanuelle ; Chaffanet, Max ; Isambert, Nicolas ; Guille, Arnaud ; Carbuccia, Nadine ; Popovici, Cornel ; Provansal, Magali ; Vicier, Cecile ; Bertucci, François ; Adélaïde, José ; Dalenc, Florence ; Rezai, Keyvan ; Birnbaum, Daniel ; Levy, Christelle

BACKGROUNDHormone-resistant HER2-negative or triple-negative advanced breast cancers (ABC) are routinely treated with paclitaxel chemotherapy. LY2780301 is a dual inhibitor of p70 ribosomal protein S6 kinase and AKT. The TAKTIC study aimed at exploring the combination of paclitaxel and LY2780301 in this population.METHODSIn this multicentric phase Ib/II trial, we enrolled patients with HER2-negative ABC, with (phase IB) or without (phase II) prior to cytotoxic treatment for advanced disease. Oral LY2780301 was administered once daily in combination with intravenous weekly paclitaxel. Primary endpoints were to determine the recommended phase II dose (RP2D) of the combination of LY2780301 with weekly paclitaxel (phase Ib), and to estimate a 6 months objective response rate (ORR) (phase II) in patients with HER2-negative ABC, both in the overall patient population and in cases with activation of the PI3K/AKT pathway (PI3KAKT+).RESULTSA total of 51 patients were enrolled; RP2D was LY2780301 500 mg QD+ paclitaxel 80 mg/m². Main drug-related adverse events noted in phase Ib included neuropathy (75% of patients, grade 3-4 in 8%), asthenia (58% of patients, no grade 3-4), and ungual toxicity (50% of patients, grade 3-4 in 25%). They were similar in the phase II part, except that 14% of patients experienced pneumonia (grade 3-4 in 6%). In the phase II part, 6-month ORR in the overall population and in PI3KAKT+ subgroup were, respectively, 63.9% [48.8-76.8] and 55% [35-73.7].CONCLUSIONCombining LY2780301 and weekly paclitaxel in patients with HER2-negative ABC was feasible with preliminary evidence of efficacy in both the overall population and the PI3KAKT+ subgroup.TRIAL REGISTRATION IDNCT01980277.

01 Nov 2017·Cancer Prevention Research

Targeting Aberrant p70S6K Activation for Estrogen Receptor–Negative Breast Cancer Prevention

Article

Author: Zhang, Qingling ; Yu, Dihua ; Wang, Xiao ; Arun, Banu ; Wang, Jinyang ; Seewaldt, Victoria L. ; Brady, Samuel W. ; Yao, Jun

AbstractThe prevention of estrogen receptor–negative (ER−) breast cancer remains a major challenge in the cancer prevention field, although antiestrogen and aromatase inhibitors have shown adequate efficacy in preventing estrogen receptor–positive (ER+) breast cancer. Lack of commonly expressed, druggable targets is a major obstacle for meeting this challenge. Previously, we detected the activation of Akt signaling pathway in atypical hyperplasic early-stage lesions of patients. In the current study, we found that Akt and the downstream 70 kDa ribosomal protein S6 kinase (p70S6K) signaling pathway was highly activated in ER− premalignant breast lesions and ER− breast cancer. In addition, p70S6K activation induced transformation of ER− human mammary epithelial cells (hMEC). Therefore, we explored the potential of targeting Akt/p70S6K in the p70S6K activated, ER− hMEC models and mouse mammary tumor models for the prevention of ER− breast cancer. We found that a clinically applicable Akt/p70S6K dual inhibitor, LY2780301, drastically decreased proliferation of hMECs with ErbB2-induced p70S6K activation via Cyclin B1 inhibition and cell-cycle blockade at G0–G1 phase, while it did not significantly reverse the abnormal acinar morphology of these hMECs. In addition, a brief treatment of LY2780301 in MMTV-neu mice that developed atypical hyperplasia (ADH) and mammary intraepithelial neoplasia (MIN) lesions with activated p70S6K was sufficient to suppress S6 phosphorylation and decrease cell proliferation in hyperplasic MECs. In summary, targeting the aberrant Akt/p70S6K activation in ER− hMEC models in vitro and in the MMTV-neu transgenic mouse model in vivo effectively inhibited Akt/S6K signaling and reduced proliferation of hMECs in vitro and ADH/MIN lesions in vivo, indicating its potential in prevention of p70S6K activated ER− breast cancer. Cancer Prev Res; 10(11); 641–50. ©2017 AACR.

100 Deals associated with LY-2780301

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Locally advanced breast cancer	Phase 2	FR	Institut Jean Paoli & Irene Calmettes	01 Jan 2014
Metastatic breast cancer	Phase 2	FR	Institut Jean Paoli & Irene Calmettes	01 Jan 2014
Non-Hodgkin Lymphoma	Phase 2	FR	Gustave Roussy, Cancer Campus, Grand Paris	01 Sep 2013
Neoplasm Metastasis	Phase 2	ES	Eli Lilly & Co.	01 Mar 2010
Solid tumor	Discovery	FR	Gustave Roussy, Cancer Campus, Grand Paris	01 Sep 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01980277 (TAKTIC, Pubmed \| Eur J Cancer Care (Engl))	Phase 2	HER2-negative breast cancer	51	LY2780301 500 mg QD+ paclitaxel 80 mg/m2	(lbrvignmuj) = vjabiabecx rtiiogbmbh (woktbgqsuf, 48.8 - 76.8)	-	12 Nov 2021
NCT01980277 (TAKTIC, ASCO2019)	Phase 2	HER2-negative breast cancer	35	LY2780301 + wP	(vdjxkpbqlv) = 50% of pts, G3-4 in 8% ndougzdyyf (kznqwyxipy ) View more	Positive	26 May 2019
NCT02018874 (INPAKT, Pubmed) Manual	Phase 1	Neoplasms	50	LY2780301+gemcitabine	(kqabecfzer) = anaemia (84%), fatigue (84%), transaminase increase (74%), thrombocytopenia (74%), nausea/vomiting (70%), neutropenia (68%) and lymphopenia (56%) nwbwgtmxjf (zcmqcnprvn ) View more	Positive	01 Sep 2017
NCT01115751 (Pubmed \| Invest New Drugs) Manual	Phase 1	Neoplasm Metastasis	32	LY2780301	(jwupykfplv) = seprsmnnlq qdfroixonj (hvjtxkvbpj ) View more	Positive	01 Jun 2015
ASCO2012	Phase 1	Solid tumor	32	LY2780301	(sqnishudzp) = prolonged stable disease for 6.5 cycles ftzvmvevpn (texpwfgxvx ) View more	-	20 May 2012