Trial: A Study of Alisertib in Combination Wit…

Trial Details

Sponsor: Puma Biotechnology, Inc. (industry)

Phase: 2

Start date: Nov. 19, 2024

Planned enrollment: 150

Trial ID: NCT06369285

More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: Alisertib (MLN8237)

Overview

Alisertib (MLN8237) is an orally bioavailable, selective inhibitor of Aurora A kinase (AURKA) originally developed by Millennium/Takeda and in-licensed by Puma Biotechnology in 2022 for further development in breast cancer and small cell lung cancer (SCLC). It has undergone multiple phase 1–2 studies across hematologic malignancies and solid tumors, with ongoing biomarker-directed evaluation in SCLC (e.g., NCT06095505). (aacrjournals.org)

Mechanism of action

Target: Aurora A serine/threonine kinase, a regulator of centrosome maturation, spindle assembly, and mitotic entry. Alisertib is a slow, tight-binding ATP-competitive AURKA inhibitor with high functional selectivity over Aurora B at clinically relevant exposures. Inhibition leads to mitotic defects, G2/M arrest, and downstream apoptosis/senescence. (aacrjournals.org)
Preclinical activity: Broad antiproliferative effects in vitro; tumor growth inhibition/regressions in xenograft models, including lymphoma; pharmacodynamic assays demonstrate AURKA pathway inhibition in vivo. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Hematologic malignancies - Relapsed/refractory aggressive B- and T-cell non-Hodgkin lymphomas (phase 2, single-agent alisertib 50 mg BID days 1–7 q21d; n=48): overall response rate (ORR) 27% (10% CR, 17% PR) across histologies. (pmc.ncbi.nlm.nih.gov)
- Peripheral T‑cell lymphoma and transformed mycosis fungoides (SWOG S1108, phase 2; n=37 treated): ORR 24% overall; within PTCL subtypes, ORR 30% (7% CR, 23% PR); median PFS 3.0 months, median OS 8.0 months. (pmc.ncbi.nlm.nih.gov)

Small cell lung cancer - Randomized, double-blind phase 2 (second-line): paclitaxel ± alisertib (n=178). Median PFS 3.32 vs 2.17 months; HR 0.77 (95% CI 0.56–1.07; p=0.113 ITT). A protocol-corrected analysis showed HR 0.71 (95% CI 0.51–0.99; p=0.038). Exploratory biomarkers suggested improved outcomes with c‑MYC expression and with mutations in RB pathway/cell-cycle regulators. (mdanderson.elsevierpure.com)
- Ongoing phase 2 monotherapy study after chemo‑immunotherapy (PUMA‑ALI‑4201; biomarker-driven; enrolling as of 2025). (dana-farber.org)

Ovarian/breast cancer - Recurrent ovarian cancer (randomized phase 2): alisertib + weekly paclitaxel vs weekly paclitaxel. Median PFS 6.7 vs 4.7 months (HR 0.75; prespecified 2‑sided α=0.20 threshold met); higher toxicity with the combination. (jamanetwork.com)

Pediatric neuroblastoma - Relapsed/refractory neuroblastoma (phase 2): alisertib + irinotecan + temozolomide. In evaluable patients, ORR ~20–21%; 1‑year PFS ~34%; activity appeared greater in MYCN‑nonamplified tumors. (pubmed.ncbi.nlm.nih.gov)

Safety

Across studies, the most common adverse events are hematologic: - Lymphoma (single agent): grade 3–4 neutropenia 63%, leukopenia 54%, anemia 35%, thrombocytopenia 33%; stomatitis 15%; febrile neutropenia 13%. (pubmed.ncbi.nlm.nih.gov) - PTCL (single agent): safety consistent with hematologic toxicity; median of 4 cycles administered (range 1–17). (pmc.ncbi.nlm.nih.gov) - SCLC (with paclitaxel): grade ≥3 drug‑related AEs in 67% with alisertib/paclitaxel vs 22% with placebo/paclitaxel; four treatment‑related deaths reported in the alisertib arm. (mdanderson.elsevierpure.com) - Ovarian cancer (with weekly paclitaxel): increased grade ≥3 neutropenia (77% vs 10%), stomatitis (25% vs 0%), and anemia (14% vs 3%) compared with paclitaxel alone. (jamanetwork.com)

TrialFetch AI Analysis

Goal: To determine the optimal oral alisertib dose, when combined with endocrine therapy, for patients with HR-positive, HER2-negative recurrent or metastatic breast cancer who have progressed after multiple prior endocrine lines and prior CDK4/6 inhibitor therapy, and to evaluate efficacy, safety, pharmacokinetics, and biomarker-defined subgroups most likely to benefit.

Patients: Adults with pathology-confirmed HR-positive, HER2-negative adenocarcinoma of the breast with recurrent or metastatic disease not amenable to cure, who have progressed on or after at least two prior lines of endocrine therapy in the metastatic/recurrent setting and have previously received a CDK4/6 inhibitor with endocrine therapy. Patients previously treated with chemotherapy for metastatic disease or with Aurora kinase inhibitors are excluded.

Design: Randomized, multicenter, dose-optimization Phase 2 trial with three alisertib dose levels combined with a selected endocrine therapy partner. Approximately 150 participants will be enrolled and assigned to 30 mg, 40 mg, or 50 mg alisertib cohorts to compare activity, tolerability, and pharmacokinetics. Biomarker analyses will explore subgroups with enhanced benefit.

Treatments: Three experimental arms evaluate alisertib at 30 mg, 40 mg, or 50 mg given with investigator-selected endocrine therapy. Alisertib is an investigational, oral selective Aurora A kinase inhibitor that disrupts mitotic spindle assembly, causing cell cycle arrest and apoptosis. In metastatic breast cancer, adding alisertib to weekly paclitaxel previously improved progression-free survival versus paclitaxel alone, though with higher rates of grade 3–4 toxicities; activity has also been observed across other malignancies. The endocrine partner represents standard therapy choices for HR-positive disease and serves as the backbone to test dose-activity and tolerability of alisertib combinations.

Outcomes: Primary measures within each dose subgroup include objective response rate, duration of response, disease control rate at 24 weeks, progression-free survival, overall survival, and incidence of treatment-emergent adverse events. Secondary measures assess the same efficacy endpoints within biomarker-defined subgroups to identify populations with differential benefit.

Burden on patient: Moderate. The study involves oral alisertib plus standard endocrine therapy with routine safety labs and adverse event monitoring typical for cytostatic/cytotoxic oral agents. Expect periodic imaging for response assessment (approximately every 8–12 weeks), standard oncologic labs, and added pharmacokinetic sampling during early cycles to support dose optimization. No chemotherapy infusions are required, but clinic visits may be more frequent initially for PK and toxicity monitoring, and hematologic adverse events may necessitate additional labs or dose modifications. Travel demands are comparable to other Phase 2 combination studies but somewhat higher than endocrine therapy alone due to PK and closer early monitoring.

Last updated: Oct 2025

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Status: Withdrawn

A Phase 2 Study of Alisertib in Combination With Endocrine Therapy in Patients With HR+, HER2-negative Recurrent or Metastatic Breast Cancer

Trial Details

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Alisertib (MLN8237)

Overview

Mechanism of action

Efficacy

Safety

Further reading

TrialFetch AI Analysis

Eligibility

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Sites (52)

Fundação Champalimaud

Hospital CUF Descobertas

Instituto Português Oncologia Do Porto

Instituto Português de Oncologia de Lisboa Francisco Gentil (IPO Lisboa)

Fundación Instituto Valenciano de Oncología (IVO)

Hospital Clínico Universitario de Valencia

Hospital Clínico de Barcelona

Hospital General Universitario Dr. Balmis

Hospital San Cecilio

Hospital San Pedro de Alcántara

Hospital Universitario Arnau de Vilanova

Hospital Universitario Fundación Jiménez Díaz

Hospital Universitario Juan Ramon Jimenez

Hospital Universitario Vall d'Hebron

Hospital Universitario Virgen del Rocío

Hospital Universitario de Basurto

Hospital Universitario de Cruces

Hospital Universitario de Jaén

Alabama Oncology

Mayo Clinic Hospital

Beverly Hills Cancer Center

City of Hope at Orange County Lennar Foundation Cancer Center

LA Cancer Network

MemorialCare Orange Coast Medical Center

UCLA Department of Medicine - Hematology/Oncology

University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center

University of Colorado School of Medicine

Cancer Specialists of North Florida

Mayo Clinic Florida

Moffitt Cancer Center

Winship Cancer Institute, Emory University

The University of Chicago

University of Illinois Cancer Center

Dana-Farber Cancer Institute

Massachusetts General Hospital

Mayo Clinic

University of Minnesota, Masonic Cancer Center

Oncology Hematology Associates

Saint Luke's Cancer Institute

Washington University School of Medicine

Cancer Care Specialists

University of Rochester Medical Center

UNC Hospitals, University of North Carolina at Chapel Hill

Taylor Cancer Research Center

The Ohio State University, Stefanie Spielman Comprehensive Breast Center

Alliance Cancer Specialists

University of Pennsylvania, Abramson Cancer Center, Perelman Center for Advanced Medicine

University of Pittsburgh (UPMC)

Tennessee Oncology, Greco-Hainsworth Center for Research

Texas Oncology

Virginia Cancer Institute

Yale University, Yale Cancer Center