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

Information source: National Cancer Center, Korea
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Metastatic Breast Cancer

Intervention: RAD001 (Drug); Gemcitabine (Drug); Cisplatin (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: National Cancer Center, Korea

Official(s) and/or principal investigator(s):
In Hae Park, Doctor, Principal Investigator, Affiliation: National Cancer Center, Korea

Overall contact:
In Hae Park, Doctor, Phone: +82-31-920-1680, Email: parkih@ncc.re.kr

Summary

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.

Clinical Details

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.

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

The recommended dose of the combination of gemcitabine, cisplatin and RAD001 (everolimus) in patients with metastatic triple-negative breast cancer

Efficacy of gemcitabine and cisplatin with or without RAD001 in patients with metastatic triple-negative breast cancer by evaluating progression free survival (PFS)

Secondary outcome:

The maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gemcitabine/cisplatin/RAD001

number of patients with adverse events as a measure of safety and tolerability

objective response rate

Overall survival (OS)

check biomarkers associated with the response of RAD001: angiogenesis, metabolism, immune cells profiles

Detailed description: 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.

Eligibility

Minimum age: 20 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

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

Locations and Contacts

In Hae Park, Doctor, Phone: +82-31-920-1680, Email: parkih@ncc.re.kr

National cancer center, Goyangsi, Gyeonggido 410-769, Korea, Republic of; Recruiting
Park, doctor, Email: parkih@ncc.re.kr
Additional Information

Starting date: August 2013
Last updated: May 1, 2015

Page last updated: August 23, 2015

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