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DRUG:

MEN1611

i
Other names: MEN1611, CH5132799, PA799, MEN-1611, MEN 1611, CH 5132799, PA-799
Company:
Menarini, Roche
Drug class:
PI3K inhibitor
Related drugs:
2ms
MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (clinicaltrials.gov)
P1/2, N=29, Active, not recruiting, Menarini Group | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024
Trial completion date • Trial primary completion date • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • RAS (Rat Sarcoma Virus)
|
BRAF mutation • PIK3CA mutation • BRAF wild-type
|
Erbitux (cetuximab) • 5-fluorouracil • oxaliplatin • irinotecan • MEN1611
4ms
The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway. (PubMed, Front Oncol)
We demonstrated good efficacy of MEN1611 in NSCLC devoid of PIK3CA gene mutations but with constitutive activation of the PI3K/AKT pathway and its synergistic effect with gefitinib both in vitro and in vivo. Overall, this preclinical study indicates that the inhibitor could be a candidate for the treatment of NSCLC with an erlotinib/gefitinib-resistant phenotype and constitutive activation of the PI3K/AKT pathway, a phenotype mimicked by our model system.
Journal
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
EGFR mutation • PIK3CA mutation
|
erlotinib • gefitinib • MEN1611
7ms
MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (clinicaltrials.gov)
P1/2, N=29, Active, not recruiting, Menarini Group | N=42 --> 29
Enrollment change • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • RAS (Rat Sarcoma Virus)
|
BRAF mutation • PIK3CA mutation • BRAF wild-type
|
Erbitux (cetuximab) • 5-fluorouracil • oxaliplatin • irinotecan • MEN1611
10ms
Enrollment open • Combination therapy • Metastases
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog)
|
PIK3CA mutation
|
Halaven (eribulin mesylate) • MEN1611
10ms
B-PRECISE-01: MEN1611 With Trastuzumab (+/- Fulvestrant) in Metastatic Breast Cancer (clinicaltrials.gov)
P1, N=62, Active, not recruiting, Menarini Group | Trial completion date: Jul 2022 --> Dec 2023 | Trial primary completion date: Jul 2022 --> Dec 2023
Trial completion date • Trial primary completion date • Metastases
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
PIK3CA mutation
|
Herceptin (trastuzumab) • fulvestrant • MEN1611
11ms
Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer. (PubMed, Breast Cancer Res Treat)
The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335).
Journal
|
HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
PIK3CA mutation
|
Herceptin (trastuzumab) • Piqray (alpelisib) • taselisib (GDC-0032) • MEN1611
11ms
MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (clinicaltrials.gov)
P1/2, N=42, Active, not recruiting, Menarini Group | Recruiting --> Active, not recruiting | Trial completion date: Jul 2023 --> Oct 2023 | Trial primary completion date: Jul 2023 --> Oct 2023
Enrollment closed • Trial completion date • Trial primary completion date • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • RAS (Rat Sarcoma Virus)
|
BRAF mutation • PIK3CA mutation • BRAF wild-type
|
Erbitux (cetuximab) • 5-fluorouracil • oxaliplatin • irinotecan • MEN1611
12ms
New P2 trial • Combination therapy • Metastases
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog)
|
PIK3CA mutation
|
Halaven (eribulin mesylate) • MEN1611
1year
The oral SERD Elacestrant in combination with the PI3K inhibitor MEN1611 inhibits tumor growth in ER+/HER2- breast cancer in vitro and in PDX models (AACR 2023)
"Overall, in all the tested in vivo models the combination of Elacestrant and MEN1611 was superior in comparison to the single agents by overcoming resistance to ER inhibition potentially driven by PI3K pathway activation in PIK3CA mutated tumors. The current data support the use of Elacestrant, the first oral SERD with positive phase III results in the EMERALD trial (Bidard et al.; JCO 2022), in combination with the PI3K inhibitor MEN1611, in ER+/HER2- mBC patients harboring PIK3CA mutations and who progressed to CDK4/6i plus ET."
Combination therapy • Preclinical
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
HER-2 negative • PIK3CA mutation • ER mutation • ESR1 mutation • PIK3CA mutation + ESR1 mutation • PIK3CA mutation + ESR1 wild-type • PIK3CA wild-type+ ESR1 wild-type • CDK4 mutation
|
MEN1611 • Orserdu (elacestrant)
1year
Model-based prediction of effective target exposure for MEN1611 in combination with trastuzumab in HER2-positive advanced or metastatic breast cancer patients. (PubMed, CPT Pharmacometrics Syst Pharmacol)
A slightly lower exposure (i.e., 25% lower) was found for the 3-weekly s.c. schedule. This important outcome confirmed the adequacy of the therapeutic dose administered in the ongoing phase 1b B-PRECISE-01 study in patients with HER2+ PI3KCA mutated advanced/metastatic BC.
Journal • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 positive • PIK3CA mutation
|
Herceptin (trastuzumab) • MEN1611
1year
Emerging new treatments in HER2 positive breast cancer (SG-BCC 2023)
Trastuzumab deruxtecan (T-DXd) was approved in December 2022 by the FDA for patients with pretreated HER2- positive breast cancer based on the results of the phase III trial Destiny-Breast03 [3], showing an impressive improvement in progression-free survival with an hazard ratio of 0.33 (95% CI 0.26– 0.43, p-value<0.0001) compared to T-DM1, according to the last update presented at SABCS 2022 [4]...Besides T-DXd and SYD985, other ADCs have been or are under investigation, including, but not limited to, patritumab deruxtecan, disitamab vedotin, XMT-1522, MM-302, MEDI-4276, A166, ARX788, BAT8001 and PF-06804103...Several TKIs have been successfully developed, with tucatinib being the latest to enter clinical practice based on the results of the HER2CLIMB trial [7], with particular importance for patients with brain metastases. Other promising emerging treatments targeting HER2/3 receptors are the HER2- targeted bispecific antibodies (including, among others, KN026 and zanidatamab) and the anti-HER3 monoclonal antibodies; for both classes, clinical trials are ongoing...In the early setting, the first large, randomized, phase III trial testing the addition of an ICI (atezolizumab) to neoadjuvant dual-anti HER2 blockade and chemotherapy was negative [10]...In the phase Ib B-PRECISE-01 study (NCT03767335) the PI3 K inhibitor izorlisib (MEN1611) was tested in combination with trastuzumab ± fulvestrant in patients with HER2-positive/PIK3CA mutated metastatic breast cancer, showing a manageable safety profile with encouraging anti-tumor activity in heavily pre-treated patients (34.1% of partial responses, 2.4% complete response, 56.1% stable disease)...Thus, due to the close crosstalk between ER and HER2 receptor pathways, the simultaneous blockade of both signaling pathways represents a promising approach to prevent the onset of mechanisms of resistance. Large evidence supports the combination of endocrine and anti-HER2 therapies (often as maintenance treatment), while new strategies with novel agents (including novel SERDs, and CDK4/6i) are currently being investigated.
PD(L)-1 Biomarker • IO biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CDK4 (Cyclin-dependent kinase 4) • KLRC1 (Killer Cell Lectin Like Receptor C1)
|
PD-L1 expression • HER-2 positive • HR positive • HER-2 negative • PIK3CA mutation
|
Tecentriq (atezolizumab) • Kadcyla (ado-trastuzumab emtansine) • Enhertu (fam-trastuzumab deruxtecan-nxki) • fulvestrant • Tukysa (tucatinib) • patritumab deruxtecan (U3-1402) • Aidixi (disitamab vedotin) • MEN1611 • anbenitamab (KN026) • zanidatamab (ZW25) • anvatabart opadotin (ARX788) • Jivadco (trastuzumab duocarmazine) • trastuzumab botidotin (A166) • PF-06804103 • XMT-1522 • BAT8001 • MEDI4276
over1year
MEN1611, a PI3K inhibitor, combined with trastuzumab ± fulvestrant for HER2+/PIK3CA mutant advanced or metastatic breast cancer: updated safety and efficacy results from the ongoing phase 1b study (B-PRECISE-01) (SABCS 2022)
Median metastatic regimens 4; 71.0% had prior pertuzumab and 91.9% had prior T- DM1. Updated results from B-PRECISE-01 demonstrated that MEN1611 combined with trastuzumab ± fulvestrant continued to show a manageable safety profile with encouraging anti-tumor activity and duration of response in heavily pre-treated patients with HER2+/PIK3CA-mutated advanced or metastatic breast cancer.
Clinical • P1 data
|
HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
HER-2 positive • HR positive • PIK3CA mutation
|
Herceptin (trastuzumab) • Perjeta (pertuzumab) • fulvestrant • MEN1611
2years
B-PRECISE-01: MEN1611 With Trastuzumab (+/- Fulvestrant) in Metastatic Breast Cancer (clinicaltrials.gov)
P1, N=62, Active, not recruiting, Menarini Group | Recruiting --> Active, not recruiting
Enrollment closed
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
PIK3CA mutation
|
Herceptin (trastuzumab) • fulvestrant • MEN1611
over2years
Tumor Growth in the High Frequency Medulloblastoma Mouse Model Ptch1/Tis21 Has a Specific Activation Signature of the PI3K/AKT/mTOR Pathway and Is Counteracted by the PI3K Inhibitor MEN1611. (PubMed, Front Oncol)
Thus, PI3K/AKT/mTOR pathway activation contributes to Ptch1/Tis21 MB development and to high frequency tumorigenesis, observed when the Tis21 gene is down-regulated. MEN1611 could provide a promising therapy for MB, especially for patient with down-regulation of Btg2 (human ortholog of the murine Tis21 gene), which is frequently deregulated in Shh-type MBs.
Preclinical • Journal
|
PTCH1 (Patched 1) • EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1) • CXCL3 (C-X-C Motif Chemokine Ligand 3)
|
MEN1611
over2years
[VIRTUAL] MEN1611 in combination with cetuximab: Targeting PIK3CA mutations in RAS-wild-type patient-derived colorectal cancer xenografts (ESMO 2021)
In conclusion, in the selected genetic setting, the combination of MEN1611 with cetuximab displayed higher activity compared to single agents showing a synergistic effect in cetuximab-resistant PDX models. These data support the ongoing C-Precise phase Ib/II study investigating anti-tumor activity and safety of MEN1611 in combination with cetuximab in PIK3CAmut/N-K-RASwt/BRAFwt mCRC patients (NCT04495621).
Clinical • Combination therapy
|
KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
KRAS mutation • PIK3CA mutation • PIK3CA H1047R
|
Erbitux (cetuximab) • MEN1611
over2years
[VIRTUAL] MEN1611, a PI3K inhibitor, combined with trastuzumab (T) ± fulvestrant (F) for HER2+/PIK3CA mutant (mut) advanced or metastatic (a/m) breast cancer (BC): Safety and efficacy results from the ongoing phase Ib study (B-PRECISE-01) (ESMO 2021)
Median metastatic regimes 4; 57.1% had prior pertuzumab and 73.8% had prior T-DM1. MEN combined with T ± F shows a manageable safety profile with encouraging duration of antitumoral activity in heavily pre-treated pts with HER2+/PIK3CAmut a/m BC. Recruitment for CE is open.
Clinical • P1 data
|
HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
HR positive • PIK3CA mutation
|
Perjeta (pertuzumab) • Kadcyla (ado-trastuzumab emtansine) • fulvestrant • MEN1611
almost3years
B-PRECISE-01: MEN1611 With Trastuzumab (+/- Fulvestrant) in Metastatic Breast Cancer (clinicaltrials.gov)
P1, N=48, Recruiting, Menarini Group | Trial completion date: Jul 2020 --> Jul 2022 | Trial primary completion date: Jul 2020 --> Jul 2022
Clinical • Trial completion date • Trial primary completion date
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
PIK3CA mutation
|
Herceptin (trastuzumab) • fulvestrant • MEN1611
3years
[VIRTUAL] Dosing frequency/PD/efficacy relationship of MEN1611 in HER2 amplified, PIK3CA mutated, and refractory to Trastuzumab xenograft model of breast cancer (AACR 2021)
Moreover, efficacy evaluation showed significant tumor-regression activity in the BID group of animals compared to the QD (79% versus 43% respectively). Although further studies are needed to evaluate time-dependent drug exposure in tumor and plasma samples, these preliminary findings support the BID clinical schedule of MEN1611 in the B-PRECISE-01 clinical trial (NCT03767335).
Preclinical
|
HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
HER-2 positive • HER-2 amplification • HER-2 negative • PIK3CA mutation • PIK3CA amplification • PIK3CA C420R
|
Herceptin (trastuzumab) • MEN1611
over3years
MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (clinicaltrials.gov)
P1/2, N=42, Recruiting, Menarini Group | Not yet recruiting --> Recruiting
Clinical • Enrollment open
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
BRAF mutation • PIK3CA mutation
|
Erbitux (cetuximab) • 5-fluorouracil • oxaliplatin • irinotecan • MEN1611
over3years
Clinical • New P1/2 trial
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
BRAF mutation • PIK3CA mutation
|
Erbitux (cetuximab) • 5-fluorouracil • oxaliplatin • irinotecan • MEN1611
over3years
P1 data
|
HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
PIK3CA mutation
|
Herceptin (trastuzumab) • fulvestrant • MEN1611