Study Evaluating Two Loading Regimens of Sunitinib or Bevacizumab Alternating With Cisplatin and Gemcitabine as Induction Therapy for Locally Advanced Nasopharyngeal Carcinoma (NPC)

NCT01309633 | Completed Phase 2

• 1 other identifier: NP01/27/10
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

\- Hypothesis We hypothesise that intermittent dosing of the anti-angiogenic RTKI sunitinib or bevacizumab prior to systemic cisplatin and gemcitabine chemotherapy to transiently "normalise" tumour vasculature in patients with locally advanced or metastatic NPC will allow greater efficiency in drug and oxygen delivery, thus potentiating sensitivity to chemotherapy. We hypothesise that a loading dose of sunitinib for 7 days is required to achieve this sensitization effect prior to the first cycle of chemotherapy, and that this effect can subsequently be maintained by a 7 day course of sunitinib prior to each subsequent cycle of chemotherapy. The other hypothesis tested is that bevacizumab 7 days prior to chemotherapy will achieve normalization of tumor vasculature as well, and may induce changes in the tumor microenvironment that is beneficial for antitumour effect.

Conditions

Nasopharyngeal Carcinoma

Keywords

locally advanced; metastatic

Outcome Measures

Primary Outcomes (1)

• Clinical Response

  1. Rates of clinical response (complete and partial clinical response). 2. Rates of pathological complete responses. 3. Progression-free survival. 4. Haematologic and non-haematologic toxicities, as well as serious adverse events.

  2 years

Study Arms (4)

Arm A

EXPERIMENTAL

1\) Arm A Day -6 to Day 0 (total 7 days): Sunitinib 12.5mg daily Cycles 1 and 2 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 Day 15 to Day 21: Sunitinib 12.5mg daily Cycle 3 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2

Drug: 12.5mg sunitinib with Cisplatin and Gemcitabine

Arm B

EXPERIMENTAL

Arm B Day -6 to Day 0 (total 7 days): Sunitinib 25mg daily Cycles 1 and 2 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 Day 15 to Day 21: Sunitinib 25mg daily Cycle 3 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2

Drug: 25mg Sunitinib alternating with Cisplatin and Gemcitabine

Arm C

EXPERIMENTAL

Arm C Day -7: IV bevacizumab 7.5mg/kg diluted in normal saline over 30 minutes Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 For locally advanced patients, 3 cycles of treatment will be administered. For metastatic patients, up to 6 cycles would be administered.

Drug: 7.5mg/kg Bevacizumab alternating with Cisplatin and Gemcitabine

Arm D

EXPERIMENTAL

Arm D Day -7: IV bevacizumab 2.5mg/kg diluted in normal saline over 30 minutes Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 For locally advanced patients, 3 cycles of treatment will be administered. For metastatic patients, up to 6 cycles would be administered

Drug: 2.5mg/kg Bevacizumab alternating with Cisplatin and Gemcitabine

Interventions

12.5mg sunitinib with Cisplatin and Gemcitabine DRUG

1\) Arm A Day -6 to Day 0 (total 7 days): Sunitinib 12.5mg daily Cycles 1 and 2 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 Day 15 to Day 21: Sunitinib 12.5mg daily Cycle 3 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2

Also known as: Arm A

Arm A

25mg Sunitinib alternating with Cisplatin and Gemcitabine DRUG

Arm B Day -6 to Day 0 (total 7 days): Sunitinib 25mg daily Cycles 1 and 2 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 Day 15 to Day 21: Sunitinib 25mg daily Cycle 3 - Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2

Also known as: Arm B

Arm B

7.5mg/kg Bevacizumab alternating with Cisplatin and Gemcitabine DRUG

Day -7: IV bevacizumab 7.5mg/kg diluted in normal saline over 30 minutes Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 For locally advanced patients, 3 cycles of treatment will be administered. For metastatic patients, up to 6 cycles would be administered.

Also known as: Arm C

Arm C

2.5mg/kg Bevacizumab alternating with Cisplatin and Gemcitabine DRUG

Day -7: IV bevacizumab 2.5mg/kg diluted in normal saline over 30 minutes Day 1: IV Gemcitabine 1000mg/m2 + IV Cisplatin 75mg/m2 Day 8: IV Gemcitabine 1000mg/m2 For locally advanced patients, 3 cycles of treatment will be administered. For metastatic patients, up to 6 cycles would be administered

Also known as: Arm D

Arm D

Eligibility Criteria

• Age: 21 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients may be included in the study only if they meet all of the following criteria:
• Male or female patients aged 21 years and above.
• Patients with histologically confirmed WHO Type II or III NPC.
• Tumour stage III, IVA (T4 N0-2 M0), IVB (Any T N3 M0) or IVC (Any T Any N M1) according to the American Joint Committee on Cancer (AJCC) 2010 criteria. Alternatively, patients with locally advanced recurrent or metastatic NPC for which systemic chemotherapy is indicated will be eligible.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Adequate organ function including the following:
• a. Bone marrow function i. Haemoglobin ≥ 9g/dl ii. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L iii. Platelet count ≥ 100 x 109/L.
• b. Liver function i. Bilirubin \< or = upper limit of normal (ULN) ii. Alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) \< or = 2.5x ULN iii. Alanine transaminase (ALT) and aspartate transaminase (AST) \< or = ULN iv. Prothrombin time (PT) within the normal range for the institution.
• c. Renal function i. Plasma creatinine within the normal range for the institution or calculated creatinine clearance (by the Cockcroft-Gault formula) \> 60mL/min.
• d. Serum amylase and lipase \< or = 1.5x ULN.
• Life expectancy of at least 3 months.
• Recovery from any previous drug- or procedure-related toxicity to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 Grade 0 or 1 (except alopecia), or to baseline preceding the prior treatment.
• Signed informed consent obtained before any study specific procedure. Subjects must be able to understand and be willing to sign the written informed consent.

You may not qualify if:

• Patients will be excluded from the study for any of the following reasons:
• Previous or concurrent anti-cancer chemotherapy, immunotherapy, radiotherapy or any other investigational therapy.
• Patients who cannot swallow or patients with chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the tested product.
• Any concomitant condition that could compromise the objectives of this study and/or the patient's compliance (eg. severe medical conditions such as uncontrolled infection, poorly controlled diabetes mellitus, hypercalcaemia, psychiatric disorders).
• Major thoracic and/or abdominal surgery in the preceding 3 weeks.
• Known human immunodeficiency virus (HIV) seropositivity, hepatitis B or C seropositivity.
• In the investigator's opinion, patients with a current or previous history of clinically significant liver disease within the previous 2 years.
• History of cardiac disease: congestive heart failure \> New York Heart Association (NYHA) Class II; active coronary artery disease (unstable angina \[anginal symptoms at rest\] or new-onset angina \[began within the last 3 months\] or myocardial infarction within the past 6 months). Cardiac arrhythmias requiring anti-arrhythmic therapy (β-blockers or digoxin are permitted).
• Uncontrolled hypertension (failure of diastolic blood pressure to fall below 90 mmHg, despite the use of ≥ 3 anti-hypertensive drugs or systolic blood pressure greater than 150 mmHg).
• Dehydration NCI-CTCAE Grade 2 or higher.
• Subjects with serious non-healing wound, ulcer, or bone fracture.
• Subjects with arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 6 months before start of study medication.
• Subjects with renal impairment (creatinine clearance by the Cockcroft-Gault formula) ≤ 60mL/min) or on dialysis.
• Persistent proteinuria of NCI-CTCAE Grade 3 or higher (\> 3.5 g/24 hours, measured by urine protein/creatinine ratio on a random urine sample).
• Clinically significant bleeding (NCI-CTCAE Grade 3 or higher) within 30 days prior to start of study medication.

Sponsors & Collaborators

• National University Hospital, Singapore: lead

Study Sites (1)

National University Hospital

Kent Ridge, 119074, Singapore

Location

MeSH Terms

Conditions

Nasopharyngeal Carcinoma; Neoplasm Metastasis

Interventions

Sunitinib; Cisplatin; Gemcitabine

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Nasopharyngeal Neoplasms; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines

Study Officials

• Boon Cher Goh, MBBS

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: March 3, 2011
• First Posted: March 7, 2011
• Study Start: September 2, 2011
• Primary Completion: March 11, 2019
• Study Completion: March 11, 2019
• Last Updated: July 22, 2019

Record last verified: 2019-07

Locations

SG (1)