Phase Ib/II Trials of RAD001 in Triple Negative Metastatic Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by National Cancer Center, Korea
Information provided by (Responsible Party):
In Hae Park, National Cancer Center, Korea Identifier:
First received: August 28, 2013
Last updated: September 10, 2013
Last verified: September 2013

PIK3CA active mutations are the most frequent genetic event in breast cancer, including in TNBC which presents activated PI3K/AKT signaling due to PIK3CA mutation or PTEN deficiency. TNBC cell lines having activated PI3K/AKT signaling showed a high sensitivity to PI3K/mTOR inhibitors. RAD001 is a potent mTOR complex 1 inhibitor and showed to enhance cisplatin or gemcitabine induced apoptosis by inhibiting p53 induced p21 expression.

This study consists of two parts. In a phase Ib part, investigators will explore the recommended dose of gemcitabine, cisplatin, and RAD001 combination in patients with metastatic TNBC. After completing the phase Ib part, investigators will review the data and discuss with Novartis before the start of a phase II part. In the phase II part, investigators will compare the efficacy of the gemcitabine and cisplatin with or without RAD001 in patients with metastatic TNBC.

Condition Intervention Phase
Metastatic Breast Cancer
Drug: RAD001 Afinitor everolimus
Drug: RAD001 gemcitabine
Drug: RAD001 cisplatin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib Trial of Gemcitabine and Cisplatin With RAD001 in Patients With Metastatic Triple Negative Breast Cancer Proceeding to an Open Label Randomized Phase II Trial Comparing Gemcitabine/Cisplatin With or Without RAD001.

Resource links provided by NLM:

Further study details as provided by National Cancer Center, Korea:

Primary Outcome Measures:
  • The recommended dose of the combination of gemcitabine, cisplatin and RAD001 (everolimus) in patients with metastatic triple-negative breast cancer [ Time Frame: up to 1 year ] [ Designated as safety issue: Yes ]
    phase IB part

  • Efficacy of gemcitabine and cisplatin with or without RAD001 in patients with metastatic triple-negative breast cancer by evaluating progression free survival (PFS) [ Time Frame: up to 5 years ] [ Designated as safety issue: Yes ]
    phase II part

Secondary Outcome Measures:
  • The maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gemcitabine/cisplatin/RAD001 [ Time Frame: up to 1 year ] [ Designated as safety issue: Yes ]
    phase Ib part

  • number of patients with adverse events as a measure of safety and tolerability [ Time Frame: up to 5 years ] [ Designated as safety issue: Yes ]
    phase Ib and phase II

  • objective response rate [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
    phase Ib and phase II

  • Overall survival (OS) [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
    phase Ib and phase II

  • check biomarkers associated with the response of RAD001: angiogenesis, metabolism, immune cells profiles [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
    phaseIb and phaseII

Estimated Enrollment: 116
Study Start Date: August 2013
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: RAD001
Drug: RAD001 Afinitor everolimus
Other Names:
  • Afinitor
  • everolimus
Drug: RAD001 gemcitabine
Other Name: gemcitabine
Drug: RAD001 cisplatin
Other Name: cisplatin


Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Females with histologically confirmed, metastatic or stage IV breast cancer
  • ER/PgR negative or poor (Allred score ≤ 3/8) and HER2 negative breast cancer
  • ECOG performance status 0-2
  • Age ≥ 20 years
  • Previously treated by anthracycline and taxane in adjuvant/neoadjuvant or metastatic setting
  • ≤ 2 chemotherapy regimens for metastatic disease
  • Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrolment.
  • CNS metastasis is permitted if asymptomatic and not requiring treatment with steroids and is documented to be non-progressing at study entry
  • Presence of measurable or evaluable disease by RECIST 1.1 criteria
  • Adequate hematopoietic function: Absolute granulocyte count ≥1,500/mm3, platelet ≥100,000/mm3, hemoglobin ≥ 10g/mm3
  • Adequate hepatic function: total bilirubin ≤ 1.5 x upper normal limit (UNL), AST/ALT ≤2.5 x UNL or ≤5 x UNL if presented with hepatic metastasis
  • Fasting serum cholesterol ≤ 300mg/dl and fasting triglycerides ≤ 2.5 x UNL
  • Adequate renal function: Serum creatinine ≤1.5mg/dL
  • Patients should sign a written informed consent before study entry
  • Patients with positive HBV-DNA of HBsAg at screening must initiate prophylaxis with appropriate antiviral medication at least one week prior to treatment start

Exclusion Criteria:

  • Known active CNS metastasis
  • Patients who received prior therapy with gemcitabine
  • Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites).
  • Patients with more than 3 prior chemotherapy lines for treating metastatic breast cancer.
  • Patients who received prior therapy with mTOR inhibitor or PI3K inhibitor
  • Known hypersensitivity to mTOR inhibitors, e.g. Sirolimus (rapamycin).
  • Radiotherapy within four weeks prior to enrolment, except radiotherapy to the bone for analgesic purpose or for lytic lesions at risk of fracture. Patients must have recovered from radiotherapy toxicities prior to enrolment.
  • Patients who have history of cancer other than in situ uterine cervix cancer or nonmelanotic skin cancer
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
  • Active ulceration of upper gastrointestinal tract
  • Other concurrent severe and/or uncontrolled conditions (e.g. uncontrolled diabetes mellitus, active untreated or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease including dyspnea at rest from any cause) that could cause unacceptable safety risks or compromise compliance with the protocol.
  • Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required.
  • Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates.
  • Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A at enrolment (rifabutin, rifampicin, clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, telithromycin) continuously for at least 7 days during any time period in the last 2 weeks prior to enrolment
  • Known hypersensitivity to protocol treatment
  • Pregnant or breast feeding
  • Peripheral neuropathy ≥ grade 2 (NCI CTCAE version 4.0) at randomization
  • Patients unwilling to or unable to comply with the protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01939418

Contact: In Hae Park, Doctor +82-31-920-1680

Korea, Republic of
National cancer center Recruiting
Goyangsi, Gyeonggido, Korea, Republic of, 410-769
Contact: Park, doctor   
Sponsors and Collaborators
National Cancer Center, Korea
  More Information

No publications provided

Responsible Party: In Hae Park, Principal Investigator, National Cancer Center, Korea Identifier: NCT01939418     History of Changes
Other Study ID Numbers: NCCCTS-13-670, 12491
Study First Received: August 28, 2013
Last Updated: September 10, 2013
Health Authority: South Korea: Korea Food and Drug Administration (KFDA)

Keywords provided by National Cancer Center, Korea:
metastatic breast cancer
triple negative breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Anti-Bacterial Agents
Antibiotics, Antineoplastic
Antifungal Agents processed this record on September 18, 2014