A Multicenter Phase II Pilot Open Label

NCT01830504 | Unknown Phase 2 DMC

• 1 other identifier: 2012-748
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

In France, 7-8 000 new thyroid cancer cases are diagnosed each year. Although a good overall prognosis, it is usually estimated that 10 to 20% will rescue and 5% will become metastatic. The standard treatment of advanced metastatic or recurrent thyroid cancer is limited to radioiodine therapy. It is estimated that 30 to 50% of patients will become resistant to radio iodine. Treatments options are limited in these refractory thyroid patients and long term survival is estimated to less than 10%. Nowadays, no drug is approved in this indication. The recent explosion in knowledge in tumour biology and the identification of potential biological targets in thyroid cancer led to several clinical trials with targeted therapies, mainly focused on TKI inhibitors targeting the MAPkinase pathway and/or VEGF. Preliminary results were encouraging in papillary thyroid tumors. Follicular (FTC) and poorly differentiated thyroid (PDTC) cancers account for 10% of thyroid cancer but 20-25% of cancers diagnosed at an advanced stage and near 50% of metastatic refractory thyroid cancers. These cancers with an aggressive behavior represent a major cause of death from thyroid cancer. In these subtypes, targeted therapies gave disappointing results. This may be related to the mutational profile of these tumors which is different from that of papillary cancers. Aberrant activation of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway is thought to play a fundamental role in thyroid tumorigenenesis of follicular and poorly differentiated thyroid cancers. Many genetic alterations have been, recently, identified in this pathway. PIK3CA mutations are found in 10-15% of FTC and can also occur in metastases derived from PDTC. Amplification/genomic copy gain of the PIK3CA has been identified in 24% of FTC and 42% of PDTC. Epigenetic inactivation of PTEN which negatively regulates PI3K has been shown in FTC. Moreover, RAS mutations observed in 20-40% of FTC and PDTC can activate the PI3K/AKT by interacting with the RAS-binding site of the P110 catalytic subunit of PI3K. Due to the high frequency of activation of PI3K and downstream effectors in progressive, recurrent and poorly differentiated cancers, inhibition of the PI3K signaling pathway with BKM120, a potent pan class I PI3K inhibitor, represents a particularly relevant therapeutic target and should be properly evaluated in advanced follicular and poorly differentiated thyroid carcinomas

Conditions

Thyroid Cancers

Keywords

thyroid cancers; refractory; PI3K inhibitor

Outcome Measures

Primary Outcomes (1)

• progression-free survival (PFS)

  The progression-free survival is defined as a lack of objective tumor progression and death. Tumor progression is documented by the CT or MRI scans. Progression is defined according to RECIST criteria (version 1.1.).

  at 6 months after the onset of the treatment

Secondary Outcomes (4)

• progression-free survival (PFS)

  PFS at 12 months after the onset of the treatment

• Objective tumor response (CR and PR)

  at 6 months after the onset of the treatment

• Overall survival

  at 6 months after the onset of the treatment

• safety and tolerance of BKM120 of BKM120: monitoring and recording AE and SAE, monitoring of hematology, blood chemistry and urine values, vital signs, physical examinations, skin, cardiac assessments and mood evaluation.

  After the patient has provided informed consent and until 4 weeks after the patient has stopped study participation. Assessments are performed at least every month during the first year, every 3 month until 12 months and every 4 months after this period.

Study Arms (1)

NVP-BKM120 (BKM120) PI3K inhibitor

EXPERIMENTAL

Drug: BKM120

Interventions

BKM120 DRUG

BKM 120, 100 mg/day continuously. For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are permitted in order to allow the patient to continue the study treatment. Dose level -1 : 80 mg/day continuously, Dose level -2 : 80 mg/day 5 days out of 7. All dose modifications, interruptions or discontinuations must be based on the worst preceding toxicity as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 4.03. A change from continuous schedule to intermittent (5 days out of 7) must be preceded by 2 days without treatment.

NVP-BKM120 (BKM120) PI3K inhibitor

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed differentiated follicular or poorly differentiated thyroid cancer
• Patients refractory to radio iodine: i.e.; absence of radioiodine uptake in at least one target lesion on a post-therapeutic whole body scan, presence of a target lesion after a cumulative radio-iodine activity of at least 600 mCi, patients with radio-iodine uptake who have progression of the disease within 12 months after radioactive iodine (RAI) treatment
• Metastatic or locally invasive disease
• Patients must have at least one site of measurable disease per RECIST (version 1.1.)
• Documented progression as per RECIST (version 1.1.) based on 2 comparative imagings performed within the last 12 months (+20%)
• Patients may have received two previous treatment with tyrosine kinase inhibitors but must be off treatment within at least 4 weeks
• Patient has signed the informed consent before any trial related activities and according to local guidelines
• Patient (male or female) is ≥ 18 years at the day of consenting to the study
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 which the investigator believes is stable at the time of screening
• Patient has adequate bone marrow and organ function as defined by the following laboratory values:
• Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 9.0 g/dL
• INR ≤ 1,5
• Potassium, calcium,and magnesium within normal limits (WNL) for theinstitution

You may not qualify if:

• Other histological subtypes of thyroid tumors: papillary, anaplastic, medullary, lymphoma or sarcoma
• Patient has received previous treatment with PI3K and/or mTOR inhibitors or AKT inhibitors,
• Patient has symptomatic central nervous system (CNS) metastases. Patients with controlled and asymptomatic CNS metastases may participate in this trial. The patient must have completed any prior local treatment for CNS metastases ≥ 28 days (including radiotherapy and/or surgery) prior to enrollment in this study
• Patient has a concurrent malignancy or malignancy within 3 years of study enrollment,
• Patient has a score ≥ 12 on the PHQ-9 questionnaire
• Patient selects a response of "1, 2 or 3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation
• Patient has a GAD-7 mood scale score ≥ 15
• Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation
• Patient is concurrently using other approved or investigational antineoplastic agent
• Patient who received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects of the surgery
• Patient has active cardiac disease or a history of cardiac dysfunction including any of the following:Unstable angina pectoris within 6 months prior to study entry,Symptomatic pericarditis,Documented myocardial infarction within 6 months prior to study entry,History of documented congestive heart failure,Documented cardiomyopathy
• Patient has a Left Ventricular Ejection Fraction (LVEF) \< 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
• Patient has any of the following cardiac conduction abnormalities:
• Patient is currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to randomization.

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (1)

Hospices Civils de Lyon

Lyon, 69003, France

Location

Related Publications (1)

• Borson-Chazot F, Dantony E, Illouz F, Lopez J, Niccoli P, Wassermann J, Do Cao C, Leboulleux S, Klein M, Tabarin A, Eberle MC, Benisvy D, de la Fouchardiere C, Bournaud C, Lasolle H, Delahaye A, Rabilloud M, Lapras V, Decaussin-Petrucci M, Schlumberger M. Effect of Buparlisib, a Pan-Class I PI3K Inhibitor, in Refractory Follicular and Poorly Differentiated Thyroid Cancer. Thyroid. 2018 Sep;28(9):1174-1179. doi: 10.1089/thy.2017.0663.

  PMID: 30105951 DERIVED

MeSH Terms

Conditions

Thyroid Neoplasms

Interventions

NVP-BKM120

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Study Officials

• Françoise BORSON-CHAZOT, PUPH

  Hospices Civils de Lyon

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2013
• First Posted: April 12, 2013
• Study Start: April 1, 2013
• Primary Completion: April 1, 2013
• Study Completion: January 1, 2017
• Last Updated: October 5, 2016

Record last verified: 2016-10

Locations

FR (1)