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

Sponsor

National Cancer Center, Korea (Other)

Overall Status

Terminated

CT.gov ID

NCT01939418

Collaborator

(none)

Enrollment

Location

Arm

47.9

Actual Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: RAD001 Drug: Gemcitabine Drug: Cisplatin	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

23 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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.

Actual Study Start Date :

Aug 1, 2013

Actual Primary Completion Date :

Jul 30, 2016

Actual Study Completion Date :

Jul 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RAD001 gemcitabine 800mg/m2, D1 and D8 iv. every 3 weeks. cisplatin 30mg/m2, D1 and D8 iv. every 3 weeks. RAD001 5mg QD. po.	Drug: RAD001 Afinitor 5mg qd. po. Other Names: Afinitor everolimus Drug: Gemcitabine gemcitabine 800mg/m2 iv. D1 and D8 every 3 weeks Drug: Cisplatin cisplatin 30mg/m2 iv. D1 and D8 every 3 weeks

Arm

Intervention/Treatment

Experimental: RAD001

gemcitabine 800mg/m2, D1 and D8 iv. every 3 weeks. cisplatin 30mg/m2, D1 and D8 iv. every 3 weeks. RAD001 5mg QD. po.

Drug: RAD001

Afinitor 5mg qd. po.

Other Names:

Afinitor

everolimus

Drug: Gemcitabine

gemcitabine 800mg/m2 iv. D1 and D8 every 3 weeks

Drug: Cisplatin

cisplatin 30mg/m2 iv. D1 and D8 every 3 weeks

Outcome Measures

Primary Outcome Measures

The recommended dose of the combination of gemcitabine, cisplatin and RAD001 (everolimus) in patients with metastatic triple-negative breast cancer [up to 1 year]
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) [up to 5 years]
phase II part

Secondary Outcome Measures

The maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gemcitabine/cisplatin/RAD001 [up to 1 year]
phase Ib part
number of patients with adverse events as a measure of safety and tolerability [up to 5 years]
phase Ib and phase II
objective response rate [up to 1 year]
phase Ib and phase II
Overall survival (OS) [up to 5 years]
phase Ib and phase II
check biomarkers associated with the response of RAD001: angiogenesis, metabolism, immune cells profiles [up to 5 years]
phaseIb and phaseII

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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