Efficacy Study of Sorafenib and Cyclophosphamide to Treat Neuroendocrine Tumors

NCT00605566 | Completed Phase 2 Results DMC

• 1 other identifier: SOR-NET-001
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase II clinical trial to assess the efficacy of the combination of metronomic cyclophosphamide and tailored sorafenib dosing in advanced, progressive NET. NET are highly vascular tumors, and high VEGF expression has been correlated with worse clinical and pathological characteristics as well as poor prognosis. A novel antiangiogenic approach relies on targeting not only the endothelial cells but also rendering them more sensitive to VEGFR blockade by achieving pericyte detachment. In this study, the dose of sorafenib will be titrated up to a maximum of 800mg BID based on patients' toxicity and on a novel pharmacodynamic assay that measures inhibition of molecular target(PDGFR) in patients' peripheral blood mononuclear cells. Dual VEGFR targeting is achieved by administering sorafenib plus metronomic low dose cyclophosphamide.

Conditions

Neuroendocrine Tumors

Keywords

Neuroendocrine; sorafenib; cyclophosphamide; pharmacodynamic

Outcome Measures

Primary Outcomes (2)

• Efficacy of Combination Sorafenib Plus Metronomic Cyclophosphamide in Advanced, Progressive NET, as Measured by the Objective Response Rate (ORR).

  Objective response (complete and partial) evaluated using RECIST criteria. Complete response (CR): disappearance of all clinical and radiological evidence of tumour (both target and non-target). Partial response (PR): at least a 30% decrease in the sum of longest diameter of target lesions.

  Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years

• Association Between p-Shift Changes and Treatment Efficacy of Individual Dose Adjustment of Sorafenib

  A phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells was used in order to predict clinical course and/or guide individual dose-titration. Positive pShift values denote stimulation of RAF signal transduction, whereas negative pShift values denote inhibition of RAF signal transduction as measured by flow-cytometry. Associations between pShift changes and treatment efficacy were measured using progression-free survival (PFS) and overall survival (OS).

  Assessed from start of study treatment until death, assessed up to 7 years.

Secondary Outcomes (3)

• Progression-free Survival (PFS)

  Assessed from start of study treatment until death or disease progression, whichever occurs first up to 7 years

• Overall Survival (OS)

  Assessed from start of study treatment until death, assessed up to 7 years.

• 1-year Survival Rate

  1 year

Study Arms (1)

I

EXPERIMENTAL

Patients will receive sorafenib and cyclophosphamide.

Drug: Sorafenib; Drug: Cyclophosphamide

Interventions

Sorafenib DRUG

During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.

Also known as: BAY 43-9006

I

Cyclophosphamide DRUG

During a run-in period, patient will start taking 50 mg QD of oral cyclophosphamide and 200 mg BID of sorafenib. On day 8 of run-in the patient will be evaluated for toxicity. In the absence of toxicity, the patient will be escalated to sorafenib 400 mg BID and continue on daily 50 mg of cyclophosphamide, or the patient will be informed to continue on sorafenib 200 mg BID and cyclophosphamide 50 mg QD. Dose escalation procedure will be repeated every 2 weeks until unable to tolerate the study drug, or a maximum of 800 mg BID is reached, or achievement of \> 90% inhibition of phosphorylation of PDGFR/Raf axis in PBMC. After "run-in" period, patient begins cycle 1, each cycle will last 28 days. Both cyclophosphamide and sorafenib will be taken orally.

Also known as: Cytoxan

I

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically confirmed neuroendocrine tumors
• Progressive and measurable metastatic disease
• Patients must not have disease that is currently amenable to surgery
• Life expectancy of greater than 3 months
• ECOG performance status ≤2
• Patients must have normal organ and marrow function
• Negative pregnancy test; agreement to use adequate birth control

You may not qualify if:

• Patients receiving chemotherapy or radiotherapy within last 4 weeks
• Patients that had received Sorafenib for advanced NET(neuroendocrine tumors) are not allowed
• Any other investigational agents within 4 weeks of study
• Patients with known brain metastases
• History of allergic reactions to compounds of similar chemical/biologic composition to sorafenib or cyclophosphamide
• Concurrent cancer from another primary site requiring treatment within the past 3 years
• Uncontrolled intercurrent illness
• Pregnant women and women who are breastfeeding
• HIV-positive patients receiving combination anti-retroviral therapy

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

Sorafenib; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Dr. Lillian Siu
• Organization: Princess Margaret Cancer Centre

lillian.siu@uhn.ca

Study Officials

• Lillian Siu, MD

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: January 18, 2008
• First Posted: January 31, 2008
• Study Start: January 1, 2008
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: February 19, 2019
• Results First Posted: February 19, 2019

Record last verified: 2018-10

Locations

CA (1)