Phase Ib/II Study of LY2780301 in Combination With Weekly PACLITAXEL in HER2-metastatic Breast Cancer

NCT01980277 | Terminated Phase 1 DMC

• 1 other identifier: TAKTIC - IPC 2012-008
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Phase Ib: recommended phase II dose (RP2D)

  To determine the recommended phase II dose (RP2D) of daily LY2780301 when administered orally in combination with weekly intravenous (IV) paclitaxel in HER2-negative, inoperable locally advanced or MBC patients

  Day 28

• Phase II: objective response rate (ORR)

  To estimate the efficacy of daily LY2780301 when administered orally at the RP2D in combination with weekly intravenous (IV) paclitaxel in HER2-negative, inoperable locally advanced or MBC patients, in the overall population and in patients with activation of PI3/AKT/S6 pathway

  until progression assessed up to 18 months

Secondary Outcomes (4)

• safety

  up to the end of treatment or maximum 6 months

• clinical benefit (CB)

  until progression assessed up to 18 months

• progression-free survival (PFS)

  until progression assessed up to 18 months

• pharmacokinetics

  D1, D8, D15, D22, D28 post dose

Study Arms (1)

LY2780301 + paclitaxel

EXPERIMENTAL

The following dose-levels will be investigated: * Continuous daily PO LY2780301 400 mg QD + weekly paclitaxel 70 mg/m²/week * Continuous daily PO LY2780301 400 mg QD + weekly paclitaxel 80 mg/m²/week * Continuous daily PO LY2780301 500 mg QD + weekly paclitaxel 80 mg/m²/week A dose reduction could be explored: \- Continuous daily PO LY2780301 300 mg QD + weekly paclitaxel 70 mg/m²/week

Drug: LY2780301 + paclitaxel

Interventions

LY2780301 + paclitaxel DRUG

Continuous daily PO LY2780301 (400 mg, 500 mg or 300 mg) QD + weekly paclitaxel (70 or 80 mg/m²/week) for 21 days cycle until progression or toxicity

LY2780301 + paclitaxel

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female or male patients (≥ 18 years)
• WHO/ECOG performance status ≤ 1 for phase Ib part, \< 2 for phase II part
• Patient with histologically confirmed inoperable locally advanced BC or MBC
• Patient with tumor biopsy from metastatic tissue containing more than 50% tumor cells
• Patient has known hormone receptor (ER/PR) status, positive and/or negative (local laboratory testing)
• Patient has HER2-negative disease: IHC 0, 1 + or 2+ and/or in situ hybridization (FISH, CISH, SISH) negative (local laboratory testing)
• Phase Ib: Patient has measurable or non-measurable disease according to RECIST 1.1 criteria only Phase II: Patient has measurable disease according to RECIST 1.1 criteria only
• Patient has adequate bone marrow and organ function
• Patient is able to swallow and retain oral medication
• Negative serum pregnancy test within ≤ one week before first dose for childbearing potential women and for women \< 12 months after the onset of menopause
• Males and Females of childbearing potential (FCBP) must agree to use a reliable form of contraception or to practice complete abstinence from heterosexual intercourse during the study treatment (and 3 months after the end of treatment)
• Life expectancy \> 3 months
• Affiliation to social security or beneficiary
• Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed

You may not qualify if:

• Previous treatment with AKT or PI3K inhibitor
• no previous cytotoxic treatment for metastatic or inoperable locally advanced disease (phase II part); Adjuvant/neoadjuvant therapy will be counted as prior line of therapy for metastatic/recurrent disease if the patient had a progression/recurrence within 6 months after completion of the therapy (12 months for taxane-based therapy). Previous hormonal treatment for metastatic or locally advanced disease is allowed.
• Patient with bone metastases only
• Patient has symptomatic CNS metastases; patients with asymptomatic CNS metastases may participate in this trial. The patient must have completed any prior local treatment for CNS metastases ≥ 15 days prior to the start of study treatment (including radiotherapy and/or surgery) and must have completed corticosteroid therapy.
• Patient has a concurrent malignancy or malignancy within 3 years of study enrollment
• Patient has received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study
• Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C; 3 weeks for weekly chemotherapy) prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half-lives prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who have undergone major surgery ≤ 28 days prior to starting study drug or who have not recovered from side effects of such therapy
• Known diagnosis of human immunodeficiency virus (HIV) infection
• Patient has a known hypersensitivity to paclitaxel or other products containing Cremophor
• Patient has a contraindication to use the paclitaxel standard pre-treatment such as corticosteroids
• Patients with any peripheral neuropathy ≥ CTCAE grade 2
• Patients with diarrhea ≥ CTCAE grade 2
• Patient has active cardiac disease

Sponsors & Collaborators

• Institut Paoli-Calmettes: lead

Study Sites (2)

Centre Geroges François Leclerd

Dijon, 21079, France

Location

Institut Paoli-Calmettes

Marseille, 13008, France

Location

Related Publications (2)

• Vicier C, Sfumato P, Isambert N, Dalenc F, Robert M, Levy C, Rezai K, Provansal M, Adelaide J, Garnier S, Guille A, Carbuccia N, Popovici C, Charafe-Jauffret E, Chaffanet M, Birnbaum D, Pakradouni J, Bertucci F, Boher JM, Sabatier R, Goncalves A. 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. Eur J Cancer. 2021 Dec;159:205-214. doi: 10.1016/j.ejca.2021.09.040. Epub 2021 Nov 12.

  PMID: 34781168 RESULT

• Sabatier R, Vicier C, Garnier S, Guille A, Carbuccia N, Isambert N, Dalenc F, Robert M, Levy C, Pakradouni J, Adelaide J, Chaffanet M, Sfumato P, Mamessier E, Bertucci F, Goncalves A. 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. Mol Oncol. 2022 May;16(10):2057-2070. doi: 10.1002/1878-0261.13188. Epub 2022 Mar 30.

  PMID: 35122700 RESULT

Related Links

• official web site of the sponsor

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Anthony GONCALVES, MD

  Institut Paoli-Calmettes

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 4, 2013
• First Posted: November 8, 2013
• Study Start: January 1, 2014
• Primary Completion: May 1, 2017
• Study Completion: December 12, 2018
• Last Updated: April 21, 2026

Record last verified: 2019-01

Locations

FR (2)