Phase Ib Dose-Escalation Study of the Akt Inhibitor Ipatasertib (Ipat) with Paclitaxel (P) in Patients (Pts) with Advanced Solid Tumors

Isakoff, SJ; Infante, Jeffrey R.; Juric, Dejan; Chan, Wai Yee; Jia, Shicheng; Musib, Luna; Zhu, Jin; Meng, Raymond D.; Patel, PH; Bendell, Johanna C.

doi:10.1093/annonc/mdu331.6

Cited by 7 publications

(6 citation statements)

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“…Preclinical studies showed synergy between ipatasertib and taxanes. 13 Analysis of on-study tumour biopsy samples from a phase 1 clinical study showed robust AKT pathway inhibition by ipatasertib at clinically achievable doses. 14 …”

Section: Introductionmentioning

confidence: 99%

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Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Kim¹,

Dent²,

Im³

et al. 2017

The Lancet Oncology

404

327

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Summary Background The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. Methods In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1–21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). Findings Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5–14·1) in the ipatasertib group and 10·2 months (6·0–13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8–9·0) with ipatasertib versus 4·9 months (3·6–5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37–0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6–9·1) with ipatasertib versus 3·7 months (1·9–7·3) with placebo (stratified HR 0·59, 95% CI 0·26–1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. Interpretation Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. Funding F Hoffmann-La Roche.

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Section: Introductionmentioning

confidence: 99%

“…In breast cancer, the combination of ipatasertib (400 mg once daily, days 1–21) with paclitaxel 90 mg/m 2 per week (days 1, 8, and 15), repeated every 28 days, was well tolerated and showed radiographic responses in the phase 1b PAM4983g study. 13 …”

Section: Introductionmentioning

confidence: 99%

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Kim¹,

Dent²,

Im³

et al. 2017

The Lancet Oncology

404

327

View full text Add to dashboard Cite

show abstract

“…The combination of paclitaxel and ipatasertib was determined to be safe and well tolerated in previous Phase Ib (PAM 4983g) 32 and Phase II LOTUS studies as: ipatasertib 400 mg po daily 3 weeks on/1 week off and paclitaxel 80 mg m −2 days 1, 8, and 15 of every 4-week cycle. 15 , 33 …”

Section: Methodsmentioning

confidence: 99%

Phase I Trial of Ipatasertib Plus Carboplatin, Carboplatin/Paclitaxel, or Capecitabine and Atezolizumab in Metastatic Triple-Negative Breast Cancer

et al. 2023

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Background This trial evaluated the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic triple–negative breast cancer (mTNBC). Methods Eligibility criteria were mTNBC, RECIST 1.1 measurable disease, no prior use of platinum for metastatic disease (Arms A and B), and no prior exposure to immune checkpoint inhibitor (Arm C). Primary endpoints were safety and RP2D. Secondary endpoints were progression–free survival (PFS), response rate, and overall survival. Results RP2D for Arm A (n = 10) was ipatasertib 300 mg daily, carboplatin AUC2, and paclitaxel 80 mg m−2 days 1, 8, and 15 every 28 days. RP2D for Arm B (n = 12) was ipatasertib 400 mg daily and carboplatin AUC2 days 1, 8, and 15 every 28 days. RP2D for Arm C (n = 6) was likely ipatasertib 300 mg 21 days on 7 days off, capecitabine 750 mg m−2, twice a day, 7 days on 7 days off, and atezolizumab 840 mg days 1 and 15 every 28 days. The most common (≥10%) grade 3-4 AEs at RP2D for Arm A (N = 7 at RP2D) were neutropenia (29%), diarrhea (14%), oral mucositis (14%), and neuropathy (14%); Arm B had diarrhea (17%) and lymphopenia (25%); and Arm C had anemia, fatigue, cognitive disturbance, and maculopapular rash (17% each). Overall responses at RP2D were 29% Arm A, 25% Arm B, and 33% Arm C. PFS was 4.8, 3.9, and 8.2 months for patients on Arms A, B, and C, respectively. Conclusions Continuous dosing of ipatasertib with chemotherapy was safe and well-tolerated. Further study is warranted in understanding the role of AKT inhibition in treatment of TNBCs. Trial registration NCT03853707.

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“…Data from preclinical studies support the partnering of ipatasertib with paclitaxel for synergy. 17 Sensitivity to ipatasertib was associated with high phosphorylated AKT levels, PTEN protein loss, and mutations in PTEN or PIK3CA. 15 Similar to ipatasertib, capivasertib (AZD5363) is another highly selective, oral small molecular AKT inhibitor which binds to and inhibits all AKT isoforms.…”

Section: Preclinical Rationalementioning

confidence: 99%

Section: Pi3k/akt Inhibitionmentioning

confidence: 99%

Novel therapeutic avenues in triple-negative breast cancer: PI3K/AKT inhibition, androgen receptor blockade, and beyond

2019

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Multiomic analyses have shed light upon the molecular heterogeneity and complexity of triple-negative breast cancers (TNBCs). With increasing recognition that TNBC is not a single disease entity but encompasses different disease subtypes, a one-size-fits-all treatment paradigm has become obsolete. In this context, the inhibition of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and androgen receptor (AR) signaling pathways have emerged as potential therapeutic strategies against selected tumors. In this paper, we reviewed the preclinical rationale, predictive biomarkers, efficacy, and safety data from early phase trials, and the future directions for these two biomarker-directed treatment approaches in TNBC.

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Phase Ib Dose-Escalation Study of the Akt Inhibitor Ipatasertib (Ipat) with Paclitaxel (P) in Patients (Pts) with Advanced Solid Tumors

Cited by 7 publications

References 0 publications

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Phase I Trial of Ipatasertib Plus Carboplatin, Carboplatin/Paclitaxel, or Capecitabine and Atezolizumab in Metastatic Triple-Negative Breast Cancer

Novel therapeutic avenues in triple-negative breast cancer: PI3K/AKT inhibition, androgen receptor blockade, and beyond

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